Description:FIELD OF THE INVENTION
The present application provides improved process for the preparation of 4-Bromo-1-chloro-2-(4-ethoxyphenyl)methylbenzene and intermediates for preparing the same which is a potential intermediate for the preparation of Dapagliflozin 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. Dapagliflozin is an orally active SGLT-2 inhibitor, approved by the FDA in January,2014 in the form of oral tablets for human use under the proprietary name, FARXIGA® and whose chemical structure is the following.

Dapagliflozin 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 Dapagliflozin and their pharmaceutically acceptable salts, which are disclosed in WO2004063209A1, WO2013152476A1, WO2015040571A1, WO2016098016A1, WO2016128995A1, WO2017042683A1, US20170166547, WO2018142422A1, CN104496952A, CN104529970A, CN104961715A, CN105294624A and CN107540648A.
Several synthetic methods have been reported in the literature to prepare 4-Bromo-1-chloro-2-(4-ethoxyphenyl) methylbenzene compound of formula (I)
(I)
WO2003099836A1 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme the disadvantage of using reducing agents such as Et3SiH commercially not viable.

WO2015063726A1 discloses the below process to prepare compound of formula (I) as per the following process involves 5-bromo-2-chlorobenzoic acid is reacted with oxalyl chloride to obtain a 5-bromo-2-chlorobenzoyl chloride, which upon reaction with phenetole in the presence of aluminium chloride and reduction in the presence of sodium borohydride or triethylsilane gives the 4-Bromo-1-chloro-2-(4-ethoxyphenyl)methyl benzene. Among them, the first step using oxalyl chloride, but the inconvenience of oxalyl chloride transport, high toxicity and large protective requirements, and the higher prices, and did not use the catalyst, resulting in insufficient yield, the raw material has been incomplete reaction.
CN104478670A discloses the below process to prepare compound of formula (I) as per the following synthetic scheme, main disadvantages of this application process is Benzylation of the process used in the AIBN, the substance will produce highly toxic cyanide during the reaction, serious pollution.

CN107311847A discloses the below process to prepare compound of formula (I) as per the following synthetic scheme disadvantages of this application mainly lengthy process followed and hazardous reagents.

CN107417515A discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

Journal of Medicinal Chemistry, 51(5), 1145-1149; 2008 discloses that 5-bromo-2-chlorobenzoic acid is used as the starting material, and it is prepared by acid chloride, Friedel-Crafts acylation, and reduction. The route of this scheme is short, but the synthesis of starting materials is difficult, and the cost is high 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 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene 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 Dapagliflozin intermediate of 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 substantially pure 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene is a potential intermediate of Dapagliflozin which is cost effective, 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 substantially pure 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene disclosed herein has the following advantages over the processes described in the prior arts:
i. by using Oleum in bromination controlled all impurities like 4-bromobenzoic acid and des bromo impurity and achieved to isolate pure material;
ii. purification in water and toluene leads to high purity with minimum loss of material;
iii. single solvent used to perform the reaction and extraction;
iv. isolated high pure materials by using specific solvent like 2-methyl THF;
v. 2-methyl THF has high recovery percentage in reaction; solvent recovered under vacuum, can be reused after distillation;
vi. diglyme solvent has high recovery percentage in reaction than THF solvent; solvents recovered under vacuum, can be reused after distillation;
vii. isolated high pure materials by using specific solvents like 2-methylTHF and Diglyme;
viii. 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;
ix. reactions carried out at low temperatures reduced additional energy;
x. reduced reaction time durations faster results;
xi. better impurity profile and improved the yield, single maximum impurities are controlled at a level of not more than 0.05;
xii. 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 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene 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 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene a Dapagliflozin 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) 2-chlorobenzoic acid undergoes bromination with N-Bromo succinimide in presence of acid and catalyst and water in a suitable solvent gives 5-bromo-2-chlorobenzoic acid compound of formula (II); wherein the acids are selected from Oleum, H2SO4, HClO4, HBr and HI more preferably Oleum or H2SO4 , catalyst selected from Na2S, Li2S, K2S more preferably Na2S and the solvents are selected from toluene, benzene, acetonitrile, THF and 2-methyl THF more preferably toluene or toluene and water or mixture thereof to form compound of formula(II);

Formula (II)
b) compound of formula (II) 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 (III) 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 (III); wherein the compound of formula (III) is not isolated;

Formula (III)
c) reacting compound of formula (III) Friedel-Crafts acylation with ethoxybenzene in presence of Lewis acids like AlCl3, FeCl3, SbCl5, BF3, GaCl3, SbCl5, BiCl3 Bi(OTf)3, TiCl4 or ZnCl2 more preferably AlCl3 and solvent like chiroform, dichloroethane, carbon tetrachloride and dichloromethane, methanol, ethanol more preferably dichloromethane and methanol gives compound of formula (IV);

Formula (IV)
d) compound of formula (IV) undergoes ketoreduction with appropriate metal hydride reducing agent in presence of Lewis acid and appropriate solvent gives compound of formula (I); wherein 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);
e) optionally purifying the compound of formula (I) in a suitable solvent.
In one aspect of the present invention provides an improved process for preparation of compound of formula (I)

Formula (I)
which comprises
compound of formula (IV) undergoes ketoreduction with appropriate metal hydride reducing agent in presence of Lewis acid and appropriate solvent gives compound of formula (I); wherein 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 yet another aspect, the present invention provides a compound of Formula (II)

Formula (II)
which comprises
reacting 2-chlorobenzoic acid undergoes bromination with N-Bromo succinimide in presence of acid and catalyst, water with shoutable solvent gives compound of formula(II); wherein acids are selected form Oleum, H2SO4, HClO4, HBr and HI more preferably Oleum or H2SO4, catalyst selected from Na2S, K2S or Li2S most preferable Na2S and the solvents are selected from toluene, benzene, acetonitrile, THF and 2-methyl THF more preferably toluene or toluene and water or mixture thereof to form compound of formula(II).

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 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene a dapagliflozin intermediate compound of formula (I).

formula (I)
In one embodiment the following Scheme-1 describes the process for the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene compound of formula (I)

Scheme 1
In one embodiment, a process for the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene, said process comprising the steps of reacting 2-chlorobenzoic acid undergoes bromination with N-Bromo succinimide in presence of acid and catalyst and water and toluene gives 5-bromo-2-chlorobenzoic acid, reacting 5-bromo-2-chlorobenzoic acid with thionyl chloride in dichloromethane to provide 5-bromo-2-chlorobenzoyl chloride, reacting the obtained compound with ethoxybenzene gives compound of formula (IV), reacting compound of formula (IV) with NaBH4 in presence of AlCl3 in 2-Methyl THF or diglyme gives compound of formula(I), optionally purifying the obtained compound of formula (I).
In another embodiment, stage (a) of the present process 2-chlorobenzoic acid undergoes bromination with N-Bromo succinimide in presence of acid and catalyst and water in a suitable solvent gives 5-bromo-2-chlorobenzoic acid compound of formula (II); wherein the acids are selected from Oleum, H2SO4, HClO4, HBr and HI more preferably Oleum or H2SO4, catalyst selected from Na2S, Li2S, K2S more preferably Na2S and the solvents are selected from toluene, benzene, acetonitrile, THF and 2-methyl THF more preferably toluene or mixture thereof to form compound of formula(II);
In another embodiment, stage (b) 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 (III) 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 (III);
In another embodiment, stage (c) 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 (IV);

In another embodiment, stage (d) of the present process involves ketoreduction with appropriate metal hydride reducing agent in presence of Lewis acid and appropriate solvent gives compound of formula (I); wherein 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 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene compound of formula (I);
formula (I)
which comprises
compound of formula (IV) undergoes ketoreduction with appropriate metal hydride reducing agent in presence of Lewis acid and appropriate solvent gives compound of formula (I); wherein 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 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 temperature employed in the process of ketoreduction is carried out at a reaction temperature preferably 45 oC to 65oC to afford said compound of formula (I).

In one embodiment, the temperature employed in the process of ketoreduction is carried out at a reaction temperature preferably 50 oC to 55oC to afford said compound of formula (I).

In one embodiment, the reaction duration employed in the process of ketoreduction is carried out at a reaction duration preferably 2 hours to 6 hours to afford said compound of formula (I).

In one embodiment reaction duration employed in the process of ketoreduction is carried out at a reaction duration preferably 3 hours to 4 hours to afford said compound of formula (I).
In another embodiment, the solvents employed in the process of ketoreduction are selected from hexanes, heptanes, diethylether, diisopropylether, toluene, benzene, diglyme, monoglyme, acetonitrile, THF, 2-methyl THF, dimethylformamide, N-methylpyridine, dimethylsulfoxide, and dimethylacetamide more preferably 2-methyl THF or diglyme or mixture thereof.
In an embodiment, the solvents employed in the process of ketoreduction are selected from acetonitrile, diglyme, monoglyme, 2-methyl THF or mixture thereof.
In an embodiment, the solvent employed in the process of ketoreduction is selected from 2-methyl THF or mixture thereof.
In another embodiment, the solvent employed in the process of ketoreduction is selected from diglyme or mixture thereof.
In one embodiment, the metal hydride reducing agents employed in the process of ketoreductionare 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 more preferably sodium borohydride.
In another embodiment, the metal hydride reducing agents employed in the process of ketoreduction is selected from sodium borohydride.
In one embodiment the process for the preparation of compound of formula (II);

formula (II)
which comprises
reacting 2-chlorobenzoic acid undergoes bromination with N-Bromo succinimide in presence of acid and catalyst, water with shoutable solvent gives compound of formula(II); wherein acids are selected form Oleum, H2SO4, HClO4, HBr and HI more preferably Oleum or H2SO4, catalysts are selected from Na2S, K2S or Li2S more preferably Na2S and the solvents are selected from toluene, benzene, acetonitrile, THF and 2-methyl THF more preferably toluene or toluene and water or mixture thereof to form compound of formula(II).
In another embodiment, the acids employed in the process of bromination are selected from Oleum, H2SO4, HClO4, HBr and HI more preferably Oleum or mixture thereof.
In another embodiment, the acid employed in the process of bromination is selected from Oleum or mixture thereof.
In another embodiment, the acid employed in the process of bromination is selected from H2SO4 or mixture thereof.
In one embodiment, the catalysts employed in the process of bromination are selected from Na2S, K2S or Li2S more preferably Na2S.
In another embodiment, the catalysts employed in the process of bromination is selected from Na2S.
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 70.0 Acetonitrile SM: 1.0% 98.77 0.59
2. 100.0 80.0 THF SM: 0.1% 99.91 0.04
3. 100.0 60.0 Monoglyme SM:0.5% Impurities observed 97.45 0.95
4. 100.0 90 Diglyme SM:ND 99.93 0.04
5. 100.0 91.0 2-methyl THF SM:ND 99.96 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 0.05.
The present invention describes and also incorporates the usage of inexpensive solvents like methanol, ethanol, diglyme, monoglyme, acetonitrile, THF, 2-methyl THF, toluene and reagents like NaBH4, thionyl chloride, Na2S, Oleum, H2SO4. 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, TEA- Triethyl amine, DIPEA- Diisopropyl ethylamine, NaBH4-Sodium borohydride, NaOt-bu-Sodium territiory butoxide SOCl2- Thionylchloride, Na2SO4- Sodium sulphate, NMT- not more than, HPLC- High performance liquid chromatography Oleum- sulphur trioxide in sulfuric acid, THF-Tetrahydrofuran, 2-Methyl-THF- 2-Methyltetrahydrofuran, Na2S- Sodium sulfide, NBS- N-Bromosuccinimide, MDC- Methylene Dichloride, H2SO4- sulfuric acid, NaOH- Sodium Hydroxide, 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
Method-1.1: Preparation of 5-bromo-2-chlorobenzoic acid

To a 500mL four-necked flask, charge 100.0g of 2-chlorobenzoic acid and Oleum (500mL) and stir for 30.0mins then add lot wise N-bromosuccinimide 224.0gm (2.0eq) into the reaction mass. After 1.0hr, maintence then charge catalytic amount of sodium sulfide 1.0gm into the reaction mass. stir at 30°C for 20 minutes until the solution is clear, then add then slowly poured the solution into an 80 mL ice-water bath for crystallization to obtain crude 5-bromo-2-chlorobenzoic acid. The filter cake added to a 250 mL four-neck flask, 300.0ml of toluene and water was added, the temperature was raised to 60° C., cooled naturally, and stirred for crystallization. Filtration, washing with 20 mL of toluene aqueous solution with and drying at 50 °C for 6 hours to obtain 128.0 g of white solid, yield: 85.0%, HPLC purity 99.76%.
Method-1.2: Preparation of 5-bromo-2-chlorobenzoic acid

To a 500mL four-necked flask, charge 100.0g of 2-chlorobenzoic acid and sulphuric acid (250mL) and stir for 30.0mins then add lot wise N-bromosuccinimide 224.0gm (2.0eq) into the reaction mass. After 1.0hr, maintence then charge catalytic amount of sodium sulfide 1.0gm into the reaction mass. stir at 30°C for 20 minutes until the solution is clear, then add then slowly poured the solution into an 80 mL ice-water bath for crystallization to obtain crude 5-bromo-2-chlorobenzoic acid. The filter cake added to a 250 mL four-neck flask, 300.0ml of toluene and water was added, the temperature was raised to 60° C., cooled naturally, and stirred for crystallization. Filtration, washing with 20 mL of toluene aqueous solution with and drying at 50 °C for 6 hours to obtain 120.0 g of white solid, yield: 80.0%, HPLC purity 99.51%.
Example-2
Preparation of (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)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, 101.2gm (2.0eq) of thionyl 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, 80.0gm of anhydrous aluminum trichloride and 71.0g of Ethoxy 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 and cooled to isolate as the title product of yield 84.41, purity 99.9%.
Example-3
Method-3.1: Preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (2-Methyl THF)

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%.
Method-3.2:Preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (Diglyme)

100.0 g of 5-bromo-2-chloro-4'-ethoxybenzophenone charged in to the Diglyme (200.0ml) under nitrogen atmosphere. The reaction mass cooled to 0-5 °C 25.0 g of sodium borohydride was added into the reaction mass as lot wise, the addition was completed, and the temperature was controlled at 10-15 °C and stirred for 1 h. Add 80.0 g of aluminium trichloride, heat to 50-55° C. for 3-4 hours, and after the reaction is completed. Distilled solvent and add Toluene The reaction mass quenched 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 title product of yield 88.9%, 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
6. 100.0 70.0 Acetonitrile SM: 1.0% 98.77 0.59
7. 100.0 80.0 THF SM: 0.1% 99.91 0.04
8. 100.0 60.0 Monoglyme SM:0.5% Impurities observed 97.45 0.95
9. 100.0 90 Diglyme SM:ND 99.93 0.04
10. 100.0 91.0 2-methyl THF SM:ND 99.96 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. Improved process for the preparation of compound of formula (I)

formula (I)
which comprises
a) 2-chlorobenzoic acid undergoes bromination with N-Bromo succinimide in presence of acid and catalyst and water in a suitable solvent gives 5-bromo-2-chlorobenzoic acid compound of formula (II); wherein the acids are selected from Oleum, H2SO4, HClO4, HBr and HI more preferably Oleum or sulphuric acid, catalyst selected from Na2S, Li2S, K2S more preferably Na2S and the solvents are selected from toluene, benzene, acetonitrile, THF and 2-methyl THF more preferably toluene or mixture of toluene and water or mixture thereof to form compound of formula(II);

Formula (II)
b) compound of formula (II) 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 (III) was not isolated;

Formula (III)
c) reacting compound of formula (III) Friedel-Crafts acylation with ethoxybenzene in presence of Lewis acids with shoutable solvent gives compound of formula (IV)

Formula (IV)
d) compound of formula (IV) undergoes ketoreduction with appropriate metal hydride reducing agent in presence of Lewis acid and appropriate solvent at reaction temperature about 45oC to 65 oC gives compound of formula (I); wherein metal hydride reducing agents are selected from sodium borohydride, lithiumborohydide, sodiumcyanoborohydide and tri-n- butyltin hydride more preferably sodium borohydride and the solvents are selected from diglyme, monoglyme, acetonitrile, THF, 2-methyl THF 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);
e) optionally purifying the compound of formula (I and II) in a suitable solvent.
2. process for the preparation of compound of formula (I)

formula (I)
which comprises
compound of formula (IV) undergoes ketoreduction with appropriate metal hydride reducing agent in presence of Lewis acid and appropriate solvent at reaction temperature about 45oC to 65 oC gives compound of formula (I); wherein metal hydride reducing agents are selected from sodium borohydride, lithiumborohydide, sodiumcyanoborohydide, and tri-n- butyltin hydride more preferably sodium borohydride and the solvents are selected from diglyme, monoglyme, acetonitrile, THF, 2-methyl THF and dimethylacetamide 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).
3. The process as claimed in claim 2, wherein said ketoreduction is carried out at a reaction temperature preferably 45 oC to 65oC to afford said compound of formula (I).
4. The process as claimed in claim 2, wherein ketoreduction is carried out at a reaction temperature more preferably 50 oC to 55oC to afford said compound of formula (I).
5. The process as claimed in claim 1 and 2, wherein ketoreduction is carried out at a reaction duration preferably 2 hours to 6 hours to afford said compound of formula (I).
6. The process as claimed in claim 1 and 2, wherein ketoreduction is carried out at a reaction duration more preferably 3 hours to 4 hours to afford said compound of formula (I).
7. The process as claimed in claim 1 and 2, wherein the solvents are selected from diglyme, monoglyme, acetonitrile, THF, 2-methyl THF and dimethylacetamide more preferably 2-methyl THF or diglyme or mixture thereof.
8. The process as claimed in claim 1 and 2, wherein the solvents are selected from acetonitrile, diglyme, monoglyme, 2-methyl THF or mixture thereof.
9. The process as claimed in claim 8, wherein the solvent is selected from 2-methyl THF or mixture thereof.
10. The process as claimed in claim 8, wherein the solvent is selected from diglyme or mixture thereof.
11. The process as claimed in claim 1 and 2, wherein the metal hydride reducing agents are selected from sodium borohydride, lithiumborohydide, sodiumcyanoborohydide and tri-n- butyltin hydride more preferably sodium borohydride.
12. The process as claimed in claim 11, wherein the metal hydride reducing agents is selected from sodium borohydride.
13. process for the preparation of compound of formula (II)

formula (II)
which comprises
reacting 2-chlorobenzoic acid undergoes bromination with N-Bromo succinimide in presence of acid and catalyst, water with shoutable solvent gives compound of formula(II); wherein acids are selected form Oleum, H2SO4, HClO4, HBr and HI more preferably Oleum or H2SO4 mixture thereof, catalyst selected from Na2S, K2S or Li2S more preferably Na2S and the solvents are selected from toluene, benzene, acetonitrile, THF and 2-methyl THF more preferably toluene or mixture of toluene and water or mixture thereof to form compound of formula(II).
14. The process as claimed in claim 1 and 13, wherein the acids are selected from Oleum, H2SO4, HClO4, HBr and HI more preferably Oleum or H2SO4 or mixture thereof.
15. The process as claimed in claim 14, wherein the acids are selected from Oleum or H2SO4 or mixture thereof.
16. The process as claimed in claim 15, wherein the acid is selected from Oleum or mixture thereof.
17. The process as claimed in claim 13, wherein the catalysts are selected from Na2S, K2S or Li2S more preferably Na2S.
18. The process as claimed in claim 1 and 2, wherein the catalyst is selected from Na2S.

19. The process as claimed in claim 1, for the purification of compound of formula (II), which comprise purifying from suitable solvents are selected from toluene or water or toluene and water or mixture thereof.