DESC:FIELD OF THE INVENTION
The present application provides an improved 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 and intermediates thereof, in high yields and purity and suitable for manufacturing in commercial scale.

Formula I

BACKGROUND OF THE INVENTION
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.
Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a class of antihyperglycemic 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 TheracosBio, 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
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.
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.
WO2009026537A1 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

WO2014187365 A1 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

U.S. Patent No.7838499 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

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

All the above prior art methods for the preparation of compound of formula (I) have inherent disadvantages such as the long-time duration of reaction, extreme reaction conditions invariably resulting in the formation of low melting 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-triol with 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).

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple, 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 and intermediates thereof which is environment friendly and commercially viable by avoiding repeated cumbersome and lengthy process and purification steps.

SUMMARY OF THE INVENTION
The improved 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 intermediates disclosed herein has the following advantages over the processes described in the prior arts:
i. less number of synthetic steps to prepare bexagliflozin, which leads to the usage of less solvents, reagents thereby reducing the effluent load making it eco-friendly and economically viable;
ii. reducing the synthetic steps will decrease the time cycle which influence the cost of the product and increases the productivity;
iii. reaction time duration is high in prior art processes whereas in present invention especially DIAD process duration of reaction is less which was reduced additional energy;
iv. in the present invention avoided usage of low melting unstable tosyl protected intermediate compounds used in prior art processes;
v. THF has high recovery percentage in reaction; solvent recovered under vacuum, can be reused after distillation;
vi. 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;
vii. reactions carried out at low temperatures reduced additional energy; reduced reaction time durations faster results;
viii. the process avoids the use of tedious and cumbersome procedures like column chromatographic purifications and multiple isolations;
the present invention provides a process for preparation of (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 intermediate compounds which is faster and the overall yield of the product is increased also it is substantially pure.
In one aspect of the present invention relates to a process for the preparation of Bexagliflozin compound of Formula I comprising the steps of:
a process for the preparation of compound of Formula I or its salts, and intermediates thereof;

Formula I
which comprises:
(a) coupling of corresponding acid chloride obtained from Formula II, with ethoxy benzene of Formula III in presence of Lewis acid gives compound of Formula

Formula II Formula III Formula IV
wherein X is bromo or iodo, and
(b) compound of formula (IV) undergoes ketoreduction with appropriate organosilane or metal hydride reducing agent in presence of Lewis acid in suitable solvent gives compound of formula (V);

Formula V
where X is as defined above, and
(c) compound of formula (V) undergoes dealkylation in presence of acetic acid and aqueous hydrobromic acid gives compound of formula (VI);

Formula VI
where X is as defined above, and
(d) compound of formula VI undergoes Mitsunobu dehydration-condensation with formula B in presence of suitable reagent and appropriate solvent to form compound of Formula I; wherein the reagent is selected form DIAD or DEAD and triphenylphosphine; wherein the solvent is selected from DCM, toluene, THF, dygylme, monoglyme, acetonitrile, EtoAc, DMF, DMA, more preferably THF;

Formula B Formula VII
where X is as defined above, and
(e) coupling of the compound of Formula VII with compound of Formula D in presence of alkyl lithium to obtain compound of the Formula VIII;

Formula D Formula VIII

(f) converting the compound of Formula VIII to compound of Formula IX in presence of methane sulphonic acid and methanol;

Formula IX
(g) reducing the compound of Formula IX to obtain crude Bexagliflozin compound of Formula I in presence of reducing agent, Lewis’s acid; and
Formula I
(h) optionally purifying the compound of formula (I) in a suitable solvent or mixture of solvents thereof
DETAILED DESCRIPTION OF THE INVENTION
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.
Unless the context requires otherwise, throughout the specification which follow, 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.”
As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly indicates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention 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 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.
The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it is individually recited herein.
All processes described herein can be performed in any 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.
The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
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.
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.
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 thus fulfilling the written description that follows, and the embodiments described herein, is provided by way of illustration of an example, or examples, of embodiment's 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.
It should also be appreciated that the present invention 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.
Various terms as used herein are shown below. To the extent a term used in a claim 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.
The term, “halogen” as used herein refers to chlorine, fluorine, bromine or iodine.

The term “one-pot” or "in-situ" typically means "in the reaction mixture" or "not in isolated form" or "existing as residue".

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

In one embodiment of the present invention relates to a process for the preparation of compound of Formula I or its salts, hydrates, solvates and intermediates thereof;

Formula I
which comprises:
(d) coupling of corresponding acid chloride obtained from Formula II, with ethoxy benzene of Formula III in presence of Lewis acid gives compound of Formula
Formula II Formula III Formula IV
wherein X is bromo or iodo, and
(e) compound of formula (IV) undergoes ketoreduction with appropriate organosilane or metal hydride reducing agent in presence of Lewis acid in suitable solvent gives compound of formula (V);

Formula V
where X is as defined above, and
(f) compound of formula (V) undergoes dealkylation in presence of acetic acid and aqueous hydrobromic acid gives compound of formula (VI);

Formula VI
where X is as defined above, and
(d) compound of formula VI undergoes Mitsunobu dehydration-condensation with formula B in presence of suitable reagent and appropriate solvent to form compound of Formula I; wherein the reagent is selected form DIAD or DEAD and triphenylphosphine; wherein the solvent is selected from DCM, toluene, THF, dygylme, monoglyme, acetonitrile, EtoAc, DMF, DMA, more preferably THF;

Formula B Formula VII
where X is as defined above, and
(e) coupling of the compound of Formula VII with compound of Formula D in presence of alkyl lithium to obtain compound of the Formula VIII;

Formula D Formula VIII

(f) converting the compound of Formula VIII to compound of Formula IX in presence of methane sulphonic acid and methanol;

Formula IX
(g) reducing the compound of Formula IX to obtain crude Bexagliflozin compound of Formula I in presence of reducing agent, Lewis’s acid; and

Formula I
(h) optionally purifying the compound of formula (I) in a suitable solvent or mixture of solvents thereof.
In further embodiment of the present invention provides a process for the preparation of compound of formula VII;

Formula VII
which comprises:
where X is bromo or iodo, and
compound of formula VI undergoes Mitsunobu dehydration-condensation with formula B in presence of suitable reagent and appropriate solvent to form compound of Formula VII; wherein the reagent is selected form DIAD or DEAD and triphenylphosphine; wherein the solvent is selected from DCM, toluene, THF, diglyme, monoglyme, acetonitrile, EtOAc, DMF, DMA more preferably THF;

In another embodiment of the present invention provides a process for the preparation of compound of formula XI;

Formula XI
which comprises:
compound of formula X undergoes Mitsunobu dehydration-condensation with formula B in presence of suitable reagent and appropriate solvent to form compound of Formula XI; wherein the reagent is selected form DIAD or DEAD and triphenylphosphine; wherein the solvent is selected from DCM, toluene, THF, diglyme, monoglyme, acetonitrile, EtOAc, DMF, DMA more preferably THF

In further embodiment a process for the preparation of compound of formula XIII;

Formula XIII
which comprises:
compound of formula XII undergoes Mitsunobu dehydration-condensation with formula B in presence of suitable reagent and appropriate solvent to form compound of Formula XIII; wherein the reagent is selected form DIAD or DEAD and triphenylphosphine; wherein the solvent is selected from DCM, toluene, THF, diglyme, monoglyme, acetonitrile, EtOAc, DMF, DMA more preferably THF;

.In certain embodiment, the process as claimed in clam 1 to 4, wherein the Mitsunobu dehydration-condensation reagent is diisopropylazodicarboxylate and triphenylphosphine.
In specific embodiment, the process as claimed in claim 1 to 4, wherein the solvent for Mitsunobu dehydration-condensation is selected from DCM, toluene, THF, diglyme, monoglyme, acetonitrile, EtOAc, DMF, DMA more preferably THF or mixture thereof.
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. 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.
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.
In another embodiment, the below are the abbreviations are used in the specification.
AlCl3- Aluminium Chloride anhydrous, HCl- Hydrochloric acid, DCM-Dichloromethane, TEA- Triethyl amine, DIPEA- Diisopropyl ethylamine, DIAD-Diisopropyl azodicarboxylate DEAD-Diethyl azodicarboxylate, 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-Tetramethyl disiloxane, TBAB-tetrabutylammonium bromide, TBAF-tetrabutylammonium fluoride, NBL-n-Butyl lithium, n-BuLi-n-Butyl lithium, TBAH-tetrabutylammonium hydroxide, TEBA- Triethylbenzylammonium chloride, TMDSO-Tetramethyl disiloxane, (Et)3SiH- Triethylsilane, MDC-Methylene Dichloride, DMSO-Dimethyl sulfoxide, NaOH-Sodium hydroxide, Na2CO3-Sodiumcarbonate, NBL-n-Butyllithium, HMPA-Hexamethyl phosphoramide, 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.
EXAMPLES
Example-1:
Preparation of (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone

100.0gm of 5-bromo-2-chlorobenzoic acid was added to 300 gm of dichloromethane, then 1.0g 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, 100.0ml of dichloromethane was added to obtain an acid chloride solution, which was stirred and dissolved to be clear for use. 500.0ml of dichloromethane, 61.0gm of anhydrous aluminium trichloride and 150.0gm of ethoxybenzene 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 500.0ml of water. Finally organic layer wash with 2x100ml of water, and dichloromethane is 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 120.0gm, purity 99.3%.
Example-2:
Synthesis of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene

100.0g of 5-bromo-2-chloro-4'-ethoxybenzophenone charged in to the 2-methyl THF (500.0ml) under nitrogen atmosphere. The reaction mass cooled to 0-5°. 25.0g 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 1h. Add 80.0 g of aluminium trichloride, heat to 50-55 °C for 3-4 hours, and after the reaction is completed. The reaction mass quenched with 500.0ml of water. Finally organic layer was washed with 2x100ml of water, and 2-Methyl THF is 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 90.1%, purity 99.9%.
Example-3:
Synthesis of 4-(5-bromo-2-chlorobenzyl)phenol

a solution of 14.8 g 4-bromo-1-chloro-2-(4-methoxy- benzyl)-benzene in 150 ml dichloromethane is cooled in the ice bath. Then 50 ml of a 1 M solution of boron tribromide in dichloromethane are added, and the solution is stirred for 2 h at ambient temperature. The solution is then cooled in the ice bath again, and saturated potassium carbonate solution is added dropwise. At ambient temperature the mixture is adjusted with aqueous 1 M hydrochloric acid to a pH of 1, the organic phase is separated off and the aqueous phase is extracted another three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, and the solvent is removed completely. 4-(5-bromo-2-chloro-benzyl)-phenol, Yield: 13.9 g (98%)
Example-4:
Synthesis of 4-bromo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene

Example 4.1: Synthesis of 4-bromo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene
Under nitrogen, ice bath contains 4-(5-bromo-2-chlorobenzyl)phenol (10.0g, 1.0mol) and 2-cyclopropoxyethan-1-ol(5.0gm,1.2eq) in THF solution (30mL). Add PPh3 (0.67g, 2.55mmol), and then add DIAD (0.12mL, 1.3mmol) dropwise, after reaction at 0? for 1h At room temperature overnight, concentrated to dryness, and purified by column chromatography to obtain the title compound as a white foamy solid (12.0gm, yield 93%).
Example 4.2: Synthesis of 4-bromo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene
Under nitrogen, ice bath contains 4-(5-bromo-2-chlorobenzyl) phenol (10.0g, 1.0mol) and 2-cyclopropoxyethan-1-ol(5.0gm,1.2eq) in THF solution (30mL). Add PPh3 (0.67g, 2.55mmol), and then add DEAD (0.12mL, 1.3mmol) dropwise, after reaction at 0? for 1h at room temperature overnight, concentrated to dryness, and purified by column chromatography to obtain the title compound as a white foamy solid (12.0gm, yield 93%).
Example-5:
Synthesis of 1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-iodobenzene Example 5.1: Synthesis of 1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-iodobenzene
Under nitrogen, ice bath contains 4-(2-chloro-5-iodobenzyl)phenol (10.0g, 1.0mol) and 2-cyclopropoxyethan-1-ol(5.0gm,1.2eq) in THF solution (30mL). Add PPh3 (0.67g, 2.55mmol), and then add DIAD (0.12mL, 1.3mmol) dropwise, after reaction at 0? for 1h At room temperature overnight, concentrated to dryness, and purified by column chromatography to obtain the title compound as a white foamy solid (12.0gm, yield 93%).
Example 5.2: Synthesis of 1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-iodobenzene
Under nitrogen, ice bath contains 4-(2-chloro-5-iodobenzyl)phenol (10.0g, 1.0mol) and 2-cyclopropoxyethan-1-ol(5.0gm,1.2eq) in THF solution (30mL). Add PPh3 (0.67g, 2.55mmol), and then add DEAD (0.12mL, 1.3mmol) dropwise, after reaction at 0? for 1h at room temperature overnight, concentrated to dryness, and purified by column chromatography to obtain the title compound as a white foamy solid (12.0gm, yield 93%).
Example-6
Example 6.1: 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

To the solution of l-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-nromobenzene in tetrahydrofuran, n-BuLi (2.5 mol) in hexane is 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 is stirred for 60-90 min at -75°C. After TLC complies the addition of methane sulfonic acid in methanol. The reaction mass is stirred till completion of reaction at 25°C to 35°C. After completion of reaction, the reaction is quenched by the addition of sodium carbonate and distilled out under vacuum. To the obtained residue water is added and extracted with ethylacetate. The combined ethylacetate fractions are washed with brine and dried over sodium sulfate. The reaction mixture is 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 is 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 is quenched by addition of aqueous hydrochloric acid solution. Aqueous layer is extracted with methylenechloride. Combined organic layer is washed with 5% aqueous hydrochloric acid solution followed by water and brine. The organic layer is 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-6.2: Preparation of (3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy) benzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol L-Proline

To the solution of l-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-nromobenzene in tetrahydrofuran, n-BuLi (2.5 mol) in hexane is 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- glucolactone in toluene at a rate to maintain the reaction temperature below -80°C. The solution is stirred for 60-90 min at -75°C. After TLC complies the addition of methane sulfonic acid in methanol. The reaction mass is stirred till completion of reaction at 25°C to 35°C. After completion of reaction, the reaction is quenched by the addition of sodium carbonate and distilled out under vacuum. To the obtained residue water is added and extracted with ethyl acetate. The combined ethyl acetate fractions are washed with brine and dried over sodium sulphate. The reaction mixture is 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 aluminium chloride is 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 is quenched by addition of aqueous hydrochloric acid solution. Aqueous layer is extracted with methylene dichloride. 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 (209g) HPLC purity 99.45.
,CLAIMS:1. A process for the preparation of compound of Formula I or its salts and intermediates thereof;

Formula I
which comprises:
(a) coupling of corresponding acid chloride obtained from Formula II, with ethoxy benzene of Formula III in presence of Lewis acid gives compound of Formula
Formula II Formula III Formula IV
wherein X is bromo or iodo, and
(b) compound of formula (IV) undergoes ketoreduction with appropriate organosilane or metal hydride reducing agent in presence of Lewis acid in suitable solvent gives compound of formula (V);

Formula V
where X is as defined above, and
(c) compound of formula (V) undergoes dealkylation in presence of acetic acid and aqueous hydrobromic acid gives compound of formula (VI);

Formula VI
where X is as defined above, and
(d) compound of formula VI undergoes Mitsunobu dehydration-condensation with formula B in presence of suitable reagent and appropriate solvent to form compound of Formula I; wherein the reagent is selected form DIAD or DEAD and triphenylphosphine; wherein the solvent is selected from DCM, toluene, THF, dygylme, monoglyme, acetonitrile, EtoAc, DMF, DMA, more preferably THF;

Formula B Formula VII
where X is as defined above, and
(e) coupling of the compound of Formula VII with compound of Formula D in presence of alkyl lithium to obtain compound of the Formula VIII;

Formula D Formula VIII

(f) converting the compound of Formula VIII to compound of Formula IX in presence of methane sulphonic acid and methanol;

Formula IX
(g) reducing the compound of Formula IX to obtain crude Bexagliflozin compound of Formula I in presence of reducing agent, Lewis’s acid; and

Formula I
(h) optionally purifying the compound of formula (I) in a suitable solvent or mixture of solvents thereof.
2. A process for the preparation of compound of formula VII;

Formula VII
which comprises:
where X is bromo or iodo, and
compound of formula VI undergoes Mitsunobu dehydration-condensation with formula B in presence of suitable reagent and appropriate solvent to form compound of Formula VII; wherein the reagent is selected form DIAD or DEAD and triphenylphosphine; wherein the solvent is selected from DCM, toluene, THF, diglyme, monoglyme, acetonitrile, EtOAc, DMF, DMA more preferably THF;

3. A process for the preparation of compound of formula XI;

Formula XI
which comprises:
compound of formula X undergoes Mitsunobu dehydration-condensation with formula B in presence of suitable reagent and appropriate solvent to form compound of Formula XI; wherein the reagent is selected form DIAD or DEAD and triphenylphosphine; wherein the solvent is selected from DCM, toluene, THF, diglyme, monoglyme, acetonitrile, EtOAc, DMF, DMA more preferably THF;

4. A process for the preparation of compound of formula XIII;

Formula XIII
which comprises:
compound of formula XII undergoes Mitsunobu dehydration-condensation with formula B in presence of suitable reagent and appropriate solvent to form compound of Formula XIII; wherein the reagent is selected form DIAD or DEAD and triphenylphosphine; wherein the solvent is selected from DCM, toluene, THF, diglyme, monoglyme, acetonitrile, EtOAc, DMF, DMA more preferably THF;

5. The process as claimed in claim1, wherein the said keto reduction reducing agent is selected form 1,1,3,3-tetramethyldisiloxane, (Et)3SiH, triisopropylsilane, polymethylhydrosiloxane, tris(trimethylsilyl)silane and diphenylsilane or mixture thereof.

6. The process as claimed in claim 1, wherein the solvent for keto reduction is selected from toluene, dimethyl sulfoxide, toluene and dimethyl sulfoxide mixture.

7. The process as claimed in clam 1 to 4, wherein the Mitsunobu dehydration-condensation reagent is diisopropylazodicarboxylate and triphenylphosphine.

8. The process as claimed in claim 1 to 4, wherein the solvent for Mitsunobu dehydration-condensation is selected from DCM, toluene, THF, diglyme, monoglyme, acetonitrile, EtOAc, DMF, DMA more preferably THF or mixture thereof.

9. The process as claimed in claim 1, wherein the alkyl lithium is selected from n-butyllithium, iso-butyllithium, tert- butyllithium.