DESC:FIELD OF THE INVENTION
The present application provides a process for the preparation of Bexagliflozin a SGLT2 inhibitor and its 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 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

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 (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.
U.S. Patent No.7838499 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme

WO2009026537A1 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.

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

WO2015051597 discloses the below process to prepare compound of formula (IV) 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 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-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, effective, and industrially feasible process for the 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 which is cost effective, environment friendly and commercially viable by avoiding repeated cumbersome and lengthy process and purification steps.
Another object of the present invention is to provide the 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 which avoids use of hazardous chemicals.
Another object of the present invention is to provide 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 which avoids formation of impurities.

SUMMARY OF THE INVENTION
The improved process for the 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 disclosed herein has the following advantages over the processes described in the prior arts:
i. using the cheap inexpensive alkali hydroxide and alkaline metal alkoxy base characterized in that said bases has a pKa value of from 10 to 20 in reaction is cost- effective;
ii. 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;
iii. In the present invention chemical reaction carried out in the presence of a PTC in biphasic systems, simple, costeffective and mild bases like NaOH, KOH, LiOH, Ca(OH)2 and corbonates like K2CO3, Na2CO3 and NaHCO3 can be used instead of toxic alkali metal alkoxides, amides, and hydrides.
iv. Toluene has high recovery percentage in reaction; solvent recovered under vacuum, can be reused after distillation;
v. 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;
vi. reactions carried out at low temperatures reduced additional energy;
vii. 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 cost-effective 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 compound of Formula (I) and its pharmaceutically acceptable salts thereof:

Formula (I)


Formula II Formula III
wherein,
P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo;
which comprises:
coupling of compound of Formula (II) with Formula (III) in presence of suitable base and appropriate solvent, and with or without phase transfer catalyst to obtain formula (I);
optionally purifying the compound of Formula (I) in a suitable solvent or mixture thereof.
A process for the preparation of 1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-halobenzene of Formula IV comprising the steps of:

Formula IV
(a)coupling of 2-chloro-5-halobenzoyl chloride as obtained from 2-chloro-5-halobenzoic acid Formula (V), with anisole Formula (VI) in presence of Lewis acid to obtain formula IV;

Formula V Formula VI

Formula VII
(b) reduction of the compound of Formula (VII) with TMDSO in presence of tris(pentafluro phenyl) borane to obtain compound of Formula (VIII);

Formula VIII
(c) coupling of compound of Formula (VIII) with Formula (III) in presence of suitable base and appropriate solvent, and with or without phase transfer catalyst to form formula (IV);

Formula IV
wherein,
Hal is halogen selected from bromine and iodine, P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo;
(d)optionally purifying the compound of Formula (IV) in suitable solvents or mixture thereof.
A process for the preparation of 1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-halobenzene of Formula IV comprising:

Formula VIII Formula III
(c) coupling of compound of Formula (VIII) with Formula (III) in presence of suitable base and appropriate solvent, and with or without phase transfer catalyst to to obtain formula (IV);

Formula IV
wherein,
Hal is halogen selected from bromine and iodine, P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo;
(d)optionally purifying the compound of Formula (IV) in a suitable solvents or mixture thereof.
A process for the preparation of 1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-iodobenzene of Formula (IVa) comprising:

Formula (VIIIa) Formula (IIIa)
(c) coupling of compound of Formula (VIIIa) with Formula (IIIa) in presence of suitable base and appropriate solvent, and with or without phase transfer catalyst to to obtain formula (IVa);

Formula IVa
(d)optionally purifying the compound of Formula (IVa) in a suitable solvents or mixture 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 indictates 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 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.
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 Schemes describes the process for the preparation of compound of formula (I)

Scheme 1

Scheme 2

Scheme 3

Scheme 4
In one embodiment of the present invention relates to a process for the preparation of compound of Formula (I) and its pharmaceutically acceptable salts thereof:

Formula (I)


Formula II Formula III
wherein,
P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo;
which comprises:
coupling of compound of Formula (II) with Formula (III) in presence of suitable base and appropriate solvent, and with or without phase transfer catalyst to obtain formula (I);
optionally purifying the compound of Formula (I) in a suitable solvent or mixture thereof.
In one embodiment of the present invention relates to a process for the preparation of 1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-halobenzene of Formula IV comprising the steps of:

Formula IV
(a)coupling of 2-chloro-5-halobenzoyl chloride as obtained from 2-chloro-5-halobenzoic acid Formula (V), with anisole Formula (VI) in presence of Lewis acid to obtain formula VII;

Formula V Formula VI

Formula VII
(b) reduction of the compound of Formula (VII) with TMDSO in presence of tris(pentafluro phenyl) borane to obtain compound of Formula (VIII);

Formula VIII
(c) coupling of compound of Formula (VIII) with Formula (III) in presence of suitable base and appropriate solvent, and with or without phase transfer catalyst to form formula (IV);

Formula IV
wherein,
Hal is halogen selected from bromine and iodine, P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo;
(d)optionally purifying the compound of Formula (IV) in suitable solvents or mixture thereof.
In one embodiment of the present invention relates to a process for the preparation of 1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-halobenzene of Formula IV comprising:

Formula VIII Formula III
(a) coupling of compound of Formula (VIII) with Formula (III) in presence of suitable base and appropriate solvent, and with or without phase transfer catalyst to to obtain formula (IV);

Formula IV
wherein,
Hal is halogen selected from bromine and iodine, P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo;
(b)optionally purifying the compound of Formula (I) in a suitable solvents or mixture thereof.
In one embodiment of the present invention relates to a process for the preparation of 1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-iodobenzene of Formula (IVa) comprising:

Formula (VIIIa) Formula(IIIa)
(a) coupling of compound of Formula (VIIIa) with Formula (IIIa) in presence of suitable base and appropriate solvent, and with or without phase transfer catalyst to to obtain formula (IVa);

Formula IVa
(b)optionally purifying the compound of Formula (IVa) in a suitable solvents or mixture thereof.

In step (a), coupling of 5-halo-2-chlorobenzoyl chloride obtained from Formula V 5-halo-2-chlorobenzoic acid, with anisole of Formula VI is carried out in presence of Lewis acid such as Aluminum chloride, Zinc chloride, Ferric chloride, Titanium chloride, Zirconium chloride, Boron trifluoride and the like; preferably aluminum chloride.
5-halo-2-chlorobenzoic acid of Formula V is converted into 5-halo-2-chlorobenzoyl chloride using chlorinating agent such as Oxalyl chloride, Thionyl chloride and the like. This reaction is carried out in presence of solvents selected from the group comprising of dichloromethane, chlorobenzene, nitrometane, toluene and dimethylformamide, dimethyl sulfoxide and the like.

In step (b), reduction of the compound of Formula VII in presence suitable reducing agent appropriate solvent to obtain compound of Formula VIII; Suitable reducing agent is selected from the group comprising of silane such as triethyl silane and tri isopropylsilane, tetramethyldisiloxane, tripropylsilane, diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride borohydride such as sodium borohydride; and aluminum hydride such as lithium aluminum hydride; preferably tetramethyldisiloxane, triethyl silane, sodium borohydride. This reduction is preferably carried out in the presence of a Lewis acid such as boron trifluoride etherate, tris(pentafluorophenyl) borane, trifluoroacetic acid, hydrochloric acid, and aluminum chloride. The reactions are preferably carried out in solvents selected from the group comprising of halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, acetone, toluene, dimethyl sulfoxide, dimethyl acetol, dimethylformamide, benzene, hexane, acetonitrile, ethanol, isopropanol, diglyme, monoglyme, N-methylpyrollidone, toluene and dimethyl sulfoxide mixture, tetrahydrofuran, 2-methyl THF, xylene, dioxane and mixtures thereof.

In step (c), coupling of the compound of Formula VIII is carried out with Formula III to obtain compound of the Formula IV in presence of alkali and phase transfer catalyst; wherein the alkali and alkaline metal salts are selected from carbonates such as potassium carbonate, sodium carbonate, cesiumcarbonate, hydroxides such as sodium hydroxide, potassium hydroxide, alcoholates such as methoxides, ethoxides, tert-butoxides and metal hydrides such as sodium hydride and mixture thereof; wherein the phase transfer catalyst selected fromtetrabutylammonium iodide (TBAI), tributylmethylammonium chloride, tributylmethylammonium bromide, tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), Tetrabutylammonium hydroxide (TBAH), benzyltrimethylammonium chloride, tetraoctylammonium bromide (TAOB), tetraoctylammonium chloride (TAOC), tetraoctylammonium iodide (TAOI).

Coupling of the compound of Formula VIIIa is carried out with Formula IIIa to obtain compound of the Formula IVa in presence of alkali and phase transfer catalyst; wherein the alkali and alkaline metal salts are selected from carbonates such as potassium carbonate, sodium carbonate, cesiumcarbonate, hydroxides such as sodium hydroxide, potassium hydroxide, alcoholates such as methoxides, ethoxides, tert-butoxides and metal hydrides such as sodium hydride and mixture thereof; wherein the phase transfer catalyst selected fromtetrabutylammonium iodide (TBAI), tributylmethylammonium chloride, tributylmethylammonium bromide, tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), Tetrabutylammonium hydroxide (TBAH), benzyltrimethylammonium chloride, tetraoctylammonium bromide (TAOB), tetraoctylammonium chloride (TAOC), tetraoctylammonium iodide (TAOI).

In step (d), crude compound of Formula I is optionally purified to give pure compound of Formula I. This purification is carried out by techniques already known in prior art such as crystallization. The solvent used for purification is selected from the group comprising of C1-4 alkanols, water, ethyl acetate, acetonitrile, acetone, diethyl ether and mixture thereof. Preferred solvents are selected from the group comprising of methanol, ethanol, isopropanol, water, ethyl acetate, acetonitrile, acetone, diethyl ether and mixture thereof.

Optionally purified to give pure compound of Formula IVa. This purification is carried out by techniques already known in prior art such as crystallization. The solvent used for purification is selected from the group comprising of C1-4 alkanols, water, ethyl acetate, acetonitrile, acetone, diethyl ether and mixture thereof. Preferred solvents are selected from the group comprising of methanol, ethanol, isopropanol, water, ethyl acetate, acetonitrile, acetone, diethyl ether and mixture thereof.

In another embodiment the following Scheme-1 describes the process for the preparation of 1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-iodobenzene compound of formula (IV)

Scheme 3

In another embodiment of the present invention relates to a process for the preparation of Formula IV comprising the steps of:

Formula VIII Formula III
(c) coupling of compound of Formula (VIII) with Formula (III) in presence of suitable base and appropriate solvent, and with or without phase transfer catalyst to form formula (IV);

Formula IV
wherein,
Hal is halogen selected from chlorine, bromine and iodine, P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo;
(d) optionally purifying the compound of Formula (I) in a suitable solvents or mixture thereof.

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.

In further embodiment, the alkali hydoxide and alkaline metal alkoxy base for coupling reaction is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium tert-butoxide, lithium ethoxide, lithium methoxide, potassium tert-butoxide, potassium ethoxide, potassium methoxide, sodium tert-butoxide, sodium ethoxide and sodium methoxide more preferably potassium hydroxide or mixture thereof.
In another embodiment, coupling of the compound of Formula VIII with formula III to obtain compound of Formula IV in presence of base and with or without phase transfer catalyst.
In further embodiment, coupling of the compound of Formula VIII with formula III to obtain compound of Formula IV in presence of phase transfer catalyst and base.
In further specific embodiment, coupling of the compound of Formula VIII with formula III to obtain compound of Formula IV in presence of base.
In further embodiment, the phase transfer catalyst can be selected from tetrabutylammonium iodide (TBAI), tetrabutylammonium bromide (TBAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), Triethylbenzylammonium chloride (TEBA).

In another embodiment, the said keto reduction reducing agent organosilane is selected form 1,1,3,3-tetramethyldisiloxane, (Et)3SiH, triisopropylsilane, polymethylhydrosiloxane, tris(trimethylsilyl)silane and diphenylsilane or mixture thereof.
In specific embodiment, the said dipolar aprotic solvent is selected from toluene, diglyme, monoglyme, acetone, toluene and dimethyl sulfoxide, 2-methyl THF, THF, tert-Butanol, dichloromethane, dichloroethane, isopropyl acetate, ethyl acetate, acetonitrile, xylene, toluene, benzene, heptane, cyclohexane, dioxane, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-Methyl-2-pyrrolidone or mixture thereof.
The process for the preparation of Formula I 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, MDC-Dichloromethane, DCM-Dichloromethane, TEA- Triethyl amine, DIPEA- Diisopropyl ethylamine, KOH-Potassium hydroxide, NaBH4-Sodium borohydride, NaOtbu-Sodium tertiary butoxide, SOCl2- Thionylchloride, C2O2Cl2-Oxallylchloride, MTBE-Methyl tert-butyl ether, Na2SO4- Sodium sulphate, PTC-phase-transfer catalyst, n-BuLi-n-butyl lithium, NBL-n-butyl lithium, NMT- not more than, HPLC- High performance liquid chromatography, THF-Tetrahydrofuran, 2-Methyl-THF-2-Methyltetrahydrofuran, TES-Triethylsilane, TMDS-Tetramethyl disiloxane, TBAI-tetrabutylammonium iodide, TBAB-tetrabutylammonium bromide, TBAF-tetrabutylammonium fluoride, B(C6F5)3-tris(pentafluorophenyl) borane, 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 Synthesis of 4-bromo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene
100.0 g of 4-(5-bromo-2-chlorobenzyl) phenol charged in to the toluene (500.0ml) and 100.0ml of water under nitrogen atmosphere. The reaction mass cooled to 0-5°C. Charge Sodium hydroxide (23.0gm, 2.2eq) was added in to the reaction mass at 0-5°C and then stirred for 30.0mins. Charge PTC (0.1eq) a raise the reaction mass temperature to 40-50°C.Progress of the reaction monitored by TLC. If TLC complies proceed with workup and by quenching in water and layer washed with sodium chloride .After finally dried organic layer dried sodium sulphate .Organic layer distilled under vacuum at below 45°C. After distillation crude diluted with methanol/MTBE and cooled to isolate as the tittle product of yield 90.1%, purity 99.9%.
Example-2: Synthesis of (3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Bexagliflozin)
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 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 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 chloride. 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-3: Synthesis 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(Bexagliflozin. 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 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 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 methylenechloride. Combined organic layer is 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 for to give a white solid (209 g HPLC purity 99.45% )
Example-4: Synthesis 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 (Bexagliflozin. L-Proline)
100.0 g of chlorobenzyl phenol charged in to the toluene (500.0ml) and 100.0ml of water under nitrogen atmosphere. The reaction mass cooled to 0-5°C. Charge Sodium hydroxide (40.0gm, 2.2eq) was added in to the reaction mass at 0-5°C and then stirred for 30.0mins. Charge PTC (0.1eq) a raise the reaction mass temperature to 40-50°C.Progress of the reaction monitored by TLC. If TLC complies, proceed with workup and by quenching in water and layer washed with sodium chloride .After finally dried organic layer dried sodium sulphate .Organic layer distilled under vacuum at below 45°C. After distillation, crude diluted with methanol/MTBE in L-proline and cooled to isolate as the tittle product of yield 80.5%, purity 99.6%.
,CLAIMS:1. A process for the preparation of compound of Formula (I) and its pharmaceutically acceptable salts thereof:

Formula (I)


Formula II Formula III
wherein,
P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo;
which comprises:
coupling of compound of Formula (II) with Formula (III) in presence of suitable base and appropriate solvent, and with or without phase transfer catalyst to obtain formula (I);
optionally purifying the compound of Formula (I) in a suitable solvent or mixture thereof.

2. A process for the preparation of 1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-halobenzene of Formula IV comprising the steps of:

Formula IV
(a)coupling of 2-chloro-5-halobenzoyl chloride as obtained from 2-chloro-5-halobenzoic acid Formula (V), with anisole Formula (VI) in presence of Lewis acid to obtain formula IV;

Formula V Formula VI

Formula VII
(b) reduction of the compound of Formula (VII) with TMDSO in presence of tris(pentafluro phenyl) borane to obtain compound of Formula (VIII);

Formula VIII
(c) coupling of compound of Formula (VIII) with Formula (III) in presence of suitable base and appropriate solvent, and with or without phase transfer catalyst to form formula (IV);

Formula IV
wherein,
Hal is halogen selected from bromine and iodine, P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo;
(d)optionally purifying the compound of Formula (IV) in suitable solvents or mixture thereof.

3. A process for the preparation of 1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-halobenzene of Formula IV comprising:

Formula VIII Formula III
(a) coupling of compound of Formula (VIII) with Formula (III) in presence of suitable base and appropriate solvent, and with or without phase transfer catalyst to to obtain formula (IV);

Formula IV
wherein,
Hal is halogen selected from bromine and iodine, P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo;
(b)optionally purifying the compound of Formula (I) in a suitable solvents or mixture thereof.

4. A process for the preparation of 1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-iodobenzene of Formula (IVa) comprising:

Formula (VIIIa) Formula(IIIa)
(a) coupling of compound of Formula (V) with Formula (VI) in presence of suitable base and appropriate solvent, and with or without phase transfer catalyst to to obtain formula (I);

Formula IVa
(b)optionally purifying the compound of Formula (IVa) in a suitable solvents or mixture thereof.
5. The process as claimed in claim 1 to 3, wherein the base is selected from alkali and alkaline metal salts and tertiary amine base.
6. The process as claimed in claim 5, wherein the alkali and alkaline metal salts are selected from carbonates such as potassium carbonate, sodium carbonate, cesiumcarbonate, hydroxides such as sodium hydroxide, potassium hydroxide, alcoholates such as methoxides, ethoxides, tert-butoxides and metal hydrides such as sodium hydride and mixture thereof.
7. The process as claimed in claim 6, wherein the base is selected from sodium hydroxide, potassium hydroxide, potasium tert-butoxide, sodium tert-butoxide and mixture thereof.
8. The process as claimed in claim 1 to 4, wherein the phase transfer catalyst selected fromtetrabutylammonium iodide (TBAI), tributylmethylammonium chloride, tributylmethylammonium bromide, tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), Tetrabutylammonium hydroxide (TBAH), benzyltrimethylammonium chloride, tetraoctylammonium bromide (TAOB), tetraoctylammonium chloride (TAOC), tetraoctylammonium iodide (TAOI).
9. The process as claimed in claim 1 to 4, wherein the solvent is selected from toluene, dimethyl formamide, tetrahydrofuran, acetone, water, dimethyl acetamide, N-methyl pyrollidone, dimethylsulfoxide, dichloromethane, acetonitrile, dioxane, xylene, pyridine, and alcohols such as methanol, ethanol, isopropanol, butanol and mixtures thereof.

10. The process as claimed in claim 9, wherein the solvent is selected from acetone and aromatic hydrocarbon solvent such as toluene, dimethylsulfoxide and xylene.