Description:FIELD OF THE INVENTION
The present application provides eco-friendly improved process for the preparation of (s)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy) tetrahydrofuran a empagliflozin intermediate for preparing the same which is a potential intermediate for the preparation of Empagliflozin in high yields and purity and suitable for manufacturing in commercial scale.

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. Empagliflozin is an inhibitor of the Na+- glucose co-transporter-2 (SGLT2) and is marketed under the proprietary name JARDIANCE® by Boehringer, Empagliflozin is chemically named as (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and has the following chemical structure

Empagliflozin 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 processes have been discussed in the literature for the preparation of Empagliflozin and their pharmaceutically acceptable salts, which are disclosed in WO2006117359A1, WO2006120208A1, WO2011039108A2, CN104045513A, WO2015101916A1, CN105153137 A, WO2017130217 A1, IN201621021804A and WO2019087085A1.
Several synthetic methods have been reported in the literature to prepare (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahedron compound of formula (I)
(I)

WO2006120208A1discloses the below process to prepare compound of formula (I) as per the following synthetic scheme to 5-bromo-2-chlorobenzoic acid as the starting material, by acid chloride reaction with anisole by vicryl acylation, and then (R) -3-iodine tetrahedron alkylation, reduction obtained. The synthesis scheme is also difficult to synthesize starting materials, high cost and high price.

CN111253346A discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

CN107311962A discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

CN106905305A discloses the below process to prepare compound of formula (I) as per the following synthetic scheme. Using 2-chloro-5-halobenzoic acid compound 1 and phenol as raw materials, (3S)-3-[4-[(2-chloro-5- halophenyl)methyl]phenoxy]tetrahedron formula compound 5. The total yield is 85%. The preparation method has a simple process route, but the post-treatment process is relatively complicated and generates many impurities, which is not suitable for large-scale production.

CN108178751A discloses the below process to prepare compound of formula (I) as per the following synthetic scheme, with 4-hydroxybenzyl Chlorine is the starting material, which is reacted with methanesulfonyl chloride, (s)-3 hydroxy tetrahedron in turn, then reacted with 4-iodoaniline, and finally reacted with cuprous chloride after diazotization to obtain (s) -3-(4-(5-iodo-2-chlorobenzyl)phenoxy)tetrahedron. The total yield is 78.8%. Although the method is simple to operate and has a high product yield, it produces more impurities, which is harmful to the environment and is not suitable for industrial production.

WO2023005587A1 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

Organic Letters, 16 (16), 4090-4093; 2014 discloses that 5-bromo-2-chlorobenzoic acid as the starting material, the acid chloride, and (S) -3-phenol-based tetrahedron to pay acylation, reduction obtained. The program route is shorter, but the synthesis of the starting material is difficult, costly and expensive.

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 substantially pure (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahedron which is free of impurities with high yield. Therefore, still there is need for the development of commercially viable, cost-effective process for the preparation of Empagliflozin intermediate of compound of formula (I).

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a Eco-friendly, cost -effective and industrially scalable process for the preparation of (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy) tetrahedron is a potential intermediate of Empagliflozin which is cost effective, eco green and commercially viable by avoiding repeated cumbersome and lengthy process and purification steps.

SUMMARY OF THE INVENTION
The improved process for the preparation of substantially pure (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran disclosed herein has the following advantages over the processes described in the prior arts:
i. using mixture of solvents and one-pot synthesis significantly improved in yields and purity ;
ii. 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;
iii. toluene has high recovery percentage in reaction; solvent recovered under vacuum, can be reused ;
iv. 2-Methyl THF and diglyme solvent has high recovery percentage in reaction than THF solvent; solvents recovered under vacuum, can be reused after distillation;
v. better impurity profile and improved the yield, single maximum impurities are controlled at a level of not more than 0.02;
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;
viii. reduced reaction time duration faster results;
ix. the process avoids the use of tedious and cumbersome procedures like column chromatographic purification and multiple isolation.
x. one pot synthesis favoured the amputation of isolation and drying condition leads to lower time duration and tiniest equipment in large scale manufacturing
The present invention provides a process for preparation of (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran compounds which is faster and cost-effective and the overall yield of the product is increased also it is substantially pure.
The present invention provides an improved process for the preparation of substantially pure (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran a Empagliflozin intermediate compound of formula (I).

Formula (I)
In an aspect of the present application provides an improved process for preparation of compound of formula (I)

formula (I)
which comprises:
a) 5-bromo-2-chlorobenzoic acid undergoes acid to acid chloride in presence of thionyl chloride or oxalyl chloride in suitable solvent gives 5-bromo-2-chlorobenzoyl chloride compound of formula (II);

Formula (II)
b) reacting compound of formula (II) Friedel-Crafts acylation with flurobenzene in presence of Lewis acids with suitable solvent gives compound of formula (III);

Formula (III)
c) compound of formula (III) undergoes coupling reaction with (S)-tetrahydrofuran-3-ol in presence suitable alkali hydroxide or alkaline metal alkoxy base and dipolar aprotic solvents at reaction temperature gives compound of formula (IV);

Formula (IV)
d) compound of formula (IV) undergoes keto reduction with appropriate metal hydride or organosilane or metal hydride reducing agent in presence of Lewis acid and appropriate solvent at reaction temperature gives compound of formula (I);

e) Optionally purifying the compound of formula (I) in a suitable solvent.
In another aspect of the present application provides a one-pot process for the synthesis of a compound of the formula-I starting from (5-bromo-2-chlorophenyl)(4-fluorophenyl) methanone without isolation and purification of the any intermediate

formula (I)
stages, which comprises:

a) compound of formula (III) undergoes coupling reaction with (S)-tetrahydrofuran-3-ol in presence suitable alkali hydroxide or alkaline metal alkoxy base and appropriate dipolar aprotic solvents to give compound of formula (IV);

Formula (III) Formula (IV)

b) compound of formula (IV) undergoes keto reduction with appropriate organosilane and metal hydride reducing agent in presence of Lewis acid and appropriate solvent gives compound of formula (I);
c) optionally purifying the compound of formula (I) in a suitable solvent.

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.

In one embodiment the present invention particularly describes improved process for the preparation of substantially pure (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran a empagliflozin intermediate compound of formula (I).

formula (I)
In one embodiment the following Scheme-1 describes the process for the preparation of (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran compound of formula (I)

Scheme 1
In one embodiment, stage (a) of the present process acid to acid chloride in presence of thionyl chloride or oxalyl chloride in suitable solvent gives 5-bromo-2-chlorobenzoyl chloride compound of formula (II) was not isolated; wherein the solvent selected form dichloromethane, chloroform, carbon tetrachloride, methanol, ethanol, isopropyl alcohol, acetonitrile, THF and DMF to form compound of formula (II);
In another embodiment, stage (b) of the present process involves Friedel-Crafts acylation with ethoxybenzene in presence of Lewis acids like AlCl3, FeCl3, SbCl5, BF3, GaCl3, SbCl5, BiCl3 Bi(OTf)3, TiCl4 or ZnCl2 most preferable AlCl3 and solvent like chiroform, dichloroethane, carbon tetrachloride and dichloromethane, Methanol, ethanol most preferable dichloromethane and methanol gives compound of formula (III);
In another embodiment, stage (c) of the present process involves compound of formula (III) undergoes coupling reaction with (S)-tetrahydrofuran-3-ol in presence suitable base and appropriate solvent at reaction temperature about 0oC to 20oC gives compound of formula (IV). wherein base is selected from wherein the alkali hydroxide and alkaline metal alkoxy base for coupling reaction is selected from potassium hydroxide, Sodium 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; more preferably Potassium hydroxide and the solvents are selected from toluene and dimethyulsulfoxide, Tert-Butanol, Dichloromethane, Dichloroethane, Isopropyl acetate, Ethyl acetate, Acetonitrile, Toluene, DMSO, Xylene, Dioxane, DMF or mixture thereof to form compound of formula (IV);
In another embodiment, stage (d) of the present process involves ketoreduction with appropriate organosilsne is selected form 1,1,3,3-tetramethyldisiloxane, (Et)3SiH, triisopropylsilane, tris(trimethylsilyl)silane metal hydride and Polymethylhydrosiloxane reducing agent in presence of Lewis acid and appropriate solvent gives compound of formula (I); wherin metal hydride reducing agents are selected from sodium borohydride, lithiumborohydide sodiumcyanoborohydide lithium aluminum hydride, lithium diethoxyaluminum hydride, lithium triethoxyaluminum hydride, lithium tributoxyaluminum hydride, lithium dibutoxyaluminum hydride, lithium diethylaluminum hydride, lithium triethylaluminum hydride, diisobutylaluminum hydride and tri-n- butyltin hydride most preferable sodium borohydride and the solvents are selected from hexanes, heptanes, diglyme, monoglyme, diethylether, diisopropylether, toluene, benzene, acetonitrile, THF, 2-methyl THF, dimethylformamide, N-methylpyridine, dimethylsulfoxide, and dimethylacetamide and more preferably 2-methyl THF or diglyme or mixture thereof and Lewis acids are selected from AlCl3, FeCl3, SbCl5, BF3, GaCl3, SbCl5, BiCl3, Bi(OTf)3, TiCl4 or ZnCl2 more preferably AlCl3 to form compound of formula (I).
In certain embodiment, the compound of formula (I) optionally purifying in a suitable solvent.
In one embodiment, the process for the preparation of (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran compound of formula (I);
formula (I)
which comprises
compound of formula (IV) undergoes ketoreduction with appropriate organosilane or metal hydride reducing agent in presence of Lewis acid and appropriate solvent gives compound of formula (I); wherein organosilsne is selected form 1,1,3,3-tetramethyldisiloxane, (Et)3SiH, triisopropylsilane, tris(trimethylsilyl)silanemetal hydride and Polymethylhydrosiloxane reducing agents are selected from sodium borohydride, lithiumborohydide sodiumcyanoborohydide lithium aluminum hydride, lithium diethoxyaluminum hydride, lithium triethoxyaluminum hydride, lithium tributoxyaluminum hydride, lithium dibutoxyaluminum hydride, lithium diethylaluminum hydride, lithium triethylaluminum hydride, diisobutylaluminum hydride, and tri-n- butyltin hydride most preferable sodium borohydride and the solvents are selected from hexanes, heptanes, diglyme, monoglyme, diethylether, diisopropylether, toluene, benzene, acetonitrile, THF, 2-methyl THF, dimethylformamide, N-methylpyridine, dimethylsulfoxide, and dimethylacetamide and more preferably 2-methyl THF and Lewis acids are selected from AlCl3, FeCl3, SbCl5, BF3, GaCl3, SbCl5, BiCl3, Bi(OTf)3, TiCl4 or ZnCl2 more preferably AlCl3 to form compound of formula (I).

In one embodiment, the said keto reduction reducing agent organosilane is selected form 1,1,3,3-tetramethyldisiloxane,(Et)3SiH, triisopropylsilane, Polymethylhydrosiloxane, tris(trimethylsilyl)silane, NaBH4, and diphenylsilane or mixture thereof.

In one embodiment, the said keto reduction reducing agent is 1, 1,3,3-tetramethyldisiloxane and Triethylsilane

In further embodiment, the said Lewis acid is selected form Aluminum chloride, Zinc chloride, Ferric chloride, Titanium chloride, Zirconium chloride, BF3-OEt2, BF3.

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 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 specific embodiment, wherein the alkali hydoxide is potassium hydroxide.

In specific embodiment, the said dipolaraprotic 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, dioxane, dimethylformamide, dimethyl sulfoxide, dimethylacetamide N-Methyl-2-pyrrolidone or mixture thereof.

In specific embodiment, the process as claimed in claim 9, wherein the said solvent for coupling reaction is toluene and dimethyl sulfoxide.
In one embodiment the following Scheme-2 describes the one-pot process for the preparation of (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran compound of formula (I)

Scheme-2
In certain embodiment, the process for the preparation of compound of formula (I)

formula (I)
which comprises
(5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone undergoes coupling reaction with (S)-tetrahydrofuran-3-ol followed by reduction is conducted as one-pot process in presence of potassium hydroxide and solvent Toluene and dimethylsulfoxide, THF, 2-methyl THF and Dimethyl sulfoxide and mixture thereof to form compound of formula (IV) not isolated. compound of formula (IV) under goes reduction with suitable organosilane or metal hydride and Lewis acid appropriate solvent to form compound of formula(I); wherein organosilsne is selected form 1,1,3,3-tetramethyldisiloxane, (Et)3SiH, triisopropylsilane, tris(trimethylsilyl)silane, NaBH4, and diphenylsilane, metal hydride reducing agents are selected from sodium borohydride, lithiumborohydide, sodiumcyanoborohydide, and tri-n- butyltin hydride and the solvents are selected from diglyme, monoglyme, dimethyl sulfoxide, acetonitrile, toluene, THF, 2-methyl THF, Dimethyl sulfoxide and toluene, and dimethylacetamide or diglyme, monoglyme or mixture thereof and Lewis acids are selected from AlCl3, FeCl3, SbCl5, BF3, Et3SiH, GaCl3, SbCl5, BiCl3, Bi(OTf)3, TiCl4 or ZnCl2 more preferably AlCl3 to form compound of formula (I).
In certain embodiment, the present invention provides the effect of the solvent in the present invention will become better understood with reference to the following Table-1
Table-1:
S.NO INPUT
(gm) OUTPUT
(gm) Solvent
Selections
In process Purity by HPLC
Purity SMI
1. 100.0 80.0 THF SM: 0.1% 99.93 0.04
2. 10.0 6.0 Monoglyme SM:0.5% Impurities observed 97.45 0.95
3. 100.0 84 Diglyme SM:ND 99.91 0.04
4. 100.0 87 2-methyl THF SM:ND 99.96 0.02
5. 100 88 Toluene SM:ND 99.97 0.02

THF-Tetrahydrofuran
2-methyl THF-2-Methyl tetrahydrofuran
SM-starting material
ND-not detected
Diglyme - 1-Methoxy-2-(2-methoxyethoxy)ethane
SMI-single maximum impurity.
In another embodiment, the present invention provides an impurity-controlled conversion of ketoreduction i.e., compound of formula (IV) to compound of formula (I) wherein single maximum impurities are controlled at a level of not more than 0.02.
The present invention describes and also incorporates the usage of inexpensive solvents like methanol, ethanol, diglyme, monoglyme, acetonitrile, THF, 2-methyl THF, toluene.Dimethyl sulfoxide and reagents like NaBH4,Pottasium hydroxide and TMDSO thionyl chloride.The solvents which are used in this process can be recovered and reused, which makes the process economic and environment friendly.
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, DMSO-dimethylsulfoxide, NMP-N-Methyl-2-pyrrolidone, TEA-Triethyl amine, DIPEA- Diisopropyl ethylamine, KOH-Potassium hydroxide, NaOH-Sodium Hydroxide, NaBH4-Sodium borohydride, TMDS-1,1,3,3-Tetramethyldisiloxane, TMDSO-1,1,3,3-Tetramethyldisiloxane, Et3SiH-triethylsilane, NaOt-bu-Sodium territiory butoxide, SOCl2-Thionylchloride, Na2SO4- Sodium sulphate, NMT- not more than, HPLC- High performance liquid chromatography, THF-Tetrahydrofuran, 2-Methyl-THF- 2-Methyltetrahydrofuran, NBS-N-Bromosuccinimide, MDC- Methylene Dichloride, Na2CO3-Sodium Carbonate, 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 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 500.0ml 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
Method-2.1:(KOH/MDC/Tert butanol) Preparation of (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone

Under the protection of nitrogen, 500ml of dichloromethane, 100g of (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone and 35.0g of (S)-tetrahydrofuran-3-ol 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 60°C to obtain 108g (90.51%) product of title product. Product with a purity (HPLC) of 99.16% and a single maximum impurity of 0.05%
Method-2.2: (KOH/DMF) Preparation of (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone

Under the protection of nitrogen, 200ml of Dimethyl formamide, 100g of (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone and 35.0g of (S)-tetrahydrofuran-3-ol 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 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 MDC 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 113g (92.0%) product of title product. Product with a purity (HPLC) of 99.21% and a single maximum impurity of 0.05%
Method-2.3: (KOH/DMSO and toluene) Preparation of (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone

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 (S)-tetrahydrofuran-3-ol were charge 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 dried, 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 110g (92.0%) product of title product. Product with a purity (HPLC) of 99.21% and a single maximum impurity of 0.05%
Method-2.4: (KOH/2-methyl THF) Preparation of (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone

Under the protection of nitrogen, 500ml of 2-Methyl THF, 100g of (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone and 36.0g of (S)-tetrahydrofuran-3-ol were added., and the temperature was reduced to 0-5°C. Then charged 46.0 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. After the reaction was completed, the reaction solution was transferred to 300 ml water for quenching. The organic layer extracted with 2-methyl THF 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 60°C to obtain 99 g (81.3%) product of title product.
Example-3
Method-3.1: Preparation of (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran (2-MethylTHF:)

100.0 g of (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone charged in to the 2-methyl THF(500.0ml) under nitrogen atmosphere. The reaction mass cooled to 0-5°, 20.0g(2.02eq) 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 82.0 g(2.35eq) of aluminum trichloride, heat to 50-55° C. for 3-4 hours, and after the reaction is completed, The reaction mass with 500.0ml of water .Finally organic layer wash with 2x100ml of water, and 2-MethylTHF is 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%.
Method-3.2: Preparation of (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran (Diglyme:)
100.0 g of 5(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone charged in to the Diglyme (200.0ml) under nitrogen atmosphere. The reaction mass cooled to 0-5°. 25.0g 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 80.0 g of aluminum trichloride, heat to 50-55° C. for 3-4 hours, and after the reaction is completed. Distilled solvent and add Toluene The reaction mass with 500.0ml of water .Finally organic layer wash with 2x100ml of water, and toluene 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 87.9%, purity 99.9%.
Example-4
One pot synthesis of (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran:

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 (S)-tetrahydrofuran-3-ol were charge ., 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 dried, and then taken into RBF. The reaction mass cooled to 5-10°. 92.0(2.02eq) 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 92.0 g(2.16eq) of aluminium trichloride and then add 98.0gm(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 is complettion, The reaction mass with 500.0ml of water .Finally organic layer wash with 2x100ml of water, and toluene is 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
One pot synthesis of (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran

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 (S)-tetrahydrofuran-3-ol were charge, 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 dried, and then taken into RBF. The reaction mass cooled to 5-10°. 92.0 (2.02eq) 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 92.0 g(2.16eq) of aluminium trichloride and then add 39.0gm(1.28eq) Triethylsilane to the reaction mass. Raise the reaction mass temperature to 50-55° C. for 3-4 hours. Reaction is completion, The reaction mass with 500.0ml of water. Finally organic layer wash with 2x100ml of water, and toluene is 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 92.3%, purity 99.93%.
Example-6
One pot synthesis of (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran:

Under the protection of nitrogen, 500ml of 2-MethylTHF , 100g of (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone and 36.0g of (S)-tetrahydrofuran-3-ol were added., and the temperature was reduced to 0-5°C. Then charged 46.0 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. After the reaction was completed, the reaction solution was transferred to 300 ml water for quenching. The organic layer extracted with 2-methyl THF separated by standing, and the organic layer was dried, and then taken into RBF. The reaction mass cooled to 0-5°. 20.0g(2.02eq) 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 82.0 g(2.35eq) of aluminum trichloride, heat to 50-55° C. for 3-4 hours, and after the reaction is completed, The reaction mass with 500.0ml of water .Finally organic layer wash with 2x100ml of water, and 2-MethylTHF is recovered under vacuum , which can be reused after distillation. After distillation crude diluted with IPA and cooled to isolate as the tittle product of yield 90.1%, purity 99.9%.
The advantages and effect of the solvent in the present invention will become better understood with reference to the following Table-1.

Table-1:
S.No INPUT
(gm) OUTPUT
(gm) Solvent
Selections
In process Purity by HPLC
Purity SMI
1. 100.0 80.0 THF SM: 0.1% 99.93 0.04
2. 10.0 6.0 Monoglyme SM:0.5% Impurities observed 97.45 0.95
3. 100.0 84 Diglyme SM:ND 99.91 0.04
4. 100.0 87 2-methyl THF SM:ND 99.96 0.02
5. 100.0 88 Toluene SM:ND 99.97 0.02

THF-Tetrahydrofuran
2-methyl THF-2-Methyl tetrahydrofuran
SM-starting material
ND-not detected
Diglyme - 1-Methoxy-2-(2-methoxyethoxy)ethane
SMI-single maximum impurity.
, Claims:
1. A process for the preparation of compound of formula (I)

Formula (I)
which comprises:
a) 5-bromo-2-chlorobenzoic acid undergoes acid to acid chloride in presence of Thionyl chloride or Oxalyl chloride in chlorinated solvents gives 5-bromo-2-chlorobenzoyl chloride compound of formula (II);

Formula (II)
b) reacting compound of formula (II) Friedel-Crafts acylation with flurobenzene in presence of AlCl3 in chlorinated solvents gives compound of formula (III);

Formula (III)
c) compound of formula (III) undergoes coupling reaction with (S)-tetrahydrofuran-3-ol in presence appropriate alkali hydroxide and alkaline metal alkoxy base in suitable solvent gives compound of formula (IV);

Formula (IV)
d)compound of formula (IV) undergoes ketoreduction with appropriate organosilane and metal hydride reducing agent in presence of Lewis acid in appropriate solvent gives compound of formula (I);

e) optionally purifying the compound of formula (I) in a suitable solvent.

2. A one-pot process for the synthesis of a compound of formula (I) starting from (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone compound of formula (III); without isolation and purification of intermediate (formula-IV)

Formula (I)
stages, which comprises:

a) compound of formula (III) undergoes coupling reaction with (S)-tetrahydrofuran-3-ol in presence suitable alkali hydroxide and alkaline metal alkoxy base and appropriate solvents to give compound of formula (IV);

Formula (III); Formula (IV)

b) compound of formula (IV) undergoes ketoreduction with appropriate organosilane and metal hydride reducing agents in presence of Lewis acid and appropriate solvent gives compound of formula (I);

c) optionally purifying the compound of formula (I) in a suitable solvent.

3. The process as claimed in claim 1 to 2, wherein the base for coupling reaction is selected from the group comprising of alkali hydroxide and alkaline metal alkoxy base; wherein the base characterized in that said base has a pKa value of from 10 to 20.

4. The process as claimed in claim 1 to 2, wherein 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 or mixture thereof.

5. The process as claimed in claim 4, wherein the alkali hydroxide is potassium hydroxide, sodium hydroxide and alkaline metal alkoxy base is potassium tert-butoxide, sodium tert-butoxide or mixture thereof.

6. The process as claimed in claim 1 to 2, wherein the said solvent for coupling reaction is selected from dipolaraprotic solvents, toluene, dimethyl sulfoxide, diglyme, monoglyme, acetone, toluene and dimethyl sulfoxide, 2-methyl THF, THF, tert-butanol, dichloromethane, dichloroethane, acetonitrile, xylene, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or mixture thereof.

7. The process as claimed in claim 6, wherein the said solvent is toluene and dimethyl sulfoxide, tert-butanol, 2-methyl THF, dimethylformamide, dichloromethane or mixture thereof.

8. The process as claimed in claim 1 to 2, wherein the said organosilane and metal hydride reducing agent is selected form 1,1,3,3-tetramethyldisiloxane, (Et)3SiH, triisopropylsilane, tris(trimethylsilyl)silane, polymethylhydrosiloxane, diphenylsilane and NaBH4 or mixture thereof.

9. The process as claimed in claim 8, wherein the said reducing agent for ketoreduction is 1,1,3,3-tetramethyldisiloxane, (Et)3SiH and NaBH4.

10. The process as claimed in claim 1 to 2, wherein the said Lewis acid is selected form Aluminum chloride, Zinc chloride, Ferric chloride, Titanium chloride, Zirconium chloride, BF3-OEt2 and BF3.

11. The process as claimed in claim 1 to 2, wherein the said solvent for ketoreduction is selected from toluene, diglyme, monoglyme, acetone, toluene and dimethyl sulfoxide, 2-methyl THF, THF, tert-butanol, dichloromethane, dichloroethane, acetonitrile, xylene, dioxane, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methyl-2-pyrrolidone or mixture thereof.

12. The process as claimed in claim 11, wherein the said solvent for ketoreduction is selected from 2-methyl THF, toluene, diglyme, toluene and dimethyl sulfoxide or mixture thereof.