DESC:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10; rule 13)

“SUBSTANTIALLY PURE (5-BROMO-2-CHLOROPHENYL) (4-ETHOXYPHENYL) METHANONE AND PREPARATION THEREOF”

HIKAL LIMITED, an Indian Company of 3A & 3B, International Biotech Park, Hinjewadi, Pune – 411057, Maharashtra, India

The following specification describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to substantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone of formula (IV) having undesired isomer of formula (IVA) less than 1%. The invention further relates to a process for the preparation of substantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone of formula (IV),subsequently for the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene of formula (I).

BACKGROUND OF THE INVENTION
(5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanoneis a key intermediate for the preparation of compound4-bromo-1-chloro-2-(4-ethoxybenzyl) benzenewhich is further used for the preparation of various API,s specially Dapagliflozin and Ertugliflozin. It is essential to prepare 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene with high chemical purity and greater chemical yield to avoid further purification and yield loss during the preparation of API,s.The desired purity and yield of 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene is achieved by preparation of substantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone (desired isomer).

The U.S. Patentno. 6,515,117B2;(henceforth ‘117) discloses a method for producing 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene by reacting 5-bromo-2-chlorobenzoic acid withoxalyl chloride for overnight;and further reacting with ethoxy benzene in presence of Lewis acid to provide 5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone;and finally reducing with costly triethyl silane. The ‘117 also discloses theformation of ortho and para isomer of (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone), which further required recrystallization from ethanol, and resulting into low chemical yield and purity. The above patent involved costly reagents, longer reaction time, purifications, or recrystallization process, which increases overall production cost and time.

The U.S. Patent no. 9,914,724 B2(henceforth ‘724) disclosesa method for producing 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene by reacting 5-bromo-2-chlorobenzoic acid with oxalyl chloride for overnight; and further reacting with ethoxy benzene in presence of Lewis acid to provide (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone; and finally reducing with costly triethyl silane and boron trifluoride etherate. The above patent is silent on formation of undesired isomerand the purity of desired isomer.

The U.S. Patent application no. 2021/198231(henceforth ‘231) disclosesa method for producing5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanoneby reacting 5-bromo-2-chlorobenzoic acid with oxalyl chloride for 20h; and further reacting with ethoxy benzene in presence of costly titanium (IV) tetrachloride to provide 5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanonewhich required further purification using silica gel column chromatography. The above patent is silent on formation of undesired isomer and the purity of desired isomer.

The above processes, however, have one or more disadvantages, for example: (i) the use of oxalyl chloride which is costly, hazardous and difficult to handle ; (ii) longer reaction time 20-24h; (iii)excessformation of undesired isomer (5-bromo-2-chlorophenyl)(2-ethoxyphenyl)methanone; (iv) low purity of desired isomer 5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone; (v) use of column purification or multiple purification and recrystallization technique; and (vi) excess effluent generation. Thus, to overcome the above disadvantages, there is a need to develop substantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone having undesired isomer less than 1% and process for preparation thereof.Also, there is a need for preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene using substantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone having undesired isomer less than 1% in acost effective and industrially viable manner along with low effluent generation.

The inventors of the present invention have developed a substantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone having undesired isomer less than 1% and process for preparation thereof. The inventor of present invention subsequentlydeveloped a process for preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene using substantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanoneto overcome the limitations of the prior arts processes in a cost effective, industrially convenient way. The instant two-step process is easy to perform on industrial scale which further controls the formation of undesired isomerduring the reaction transformation, thereby the desired isomer is obtained with high chemical yield (>90%), greater chemical purity (>99.5%).

SUMMARY OF THE INVENTION
One aspect of the present invention is to provide a substantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone of formula (IV) having undesired isomer (IVA) less than 1%.

In another aspect, the present invention relates a process forthe preparationof substantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone of formula (IV).

In another aspect, the present invention relates to a processfor the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene of formula (I) using substantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone of formula (IV) having undesired isomer of formula (IVA) less than 1%.

In another aspect, the present invention relates to a process for the preparation of substantially puredesired compound of formula (IV)using thionyl chloride.

In another aspect, the present invention relates to a processfor the preparation of substantially pure(5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanoneof formula (IV) having undesired compound of formula (IVA) less than 1% which comprising the step of:
? reacting compound of formula (II) with thionyl chloride, in presence of catalyst; followed by reacting with ethoxy benzene in presence of Lewis acid in solvent to obtain compound of formula (IV).

In another aspect, the present invention relates to an improved processfor the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzeneof formula (I) comprising steps:

a) reactingcompound of formula (II) with thionyl chloride, in presence of catalyst; followed by reacting with ethoxy benzene in presence of Lewis acid insolventto obtain compound of formula (IV),

b) reducing compound of formula (IV) with reducing agent in presence of Lewis acid in solventto obtain compound of formula (I),where compound (IV) is used with or without purification.

Yet another aspect of the present invention is to provide an improved process for the preparation of Dapagliflozin by using 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene (I) obtained fromsubstantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone of formula (IV) having undesired isomer of formula (IVA) less than 1%. The process for preparation of Dapagliflozin is followed by a skilled person as illustrated in US 6,515,117 B2.

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more detail hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms“a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.
The term undesired isomerof formula (IVA) used herein, refers to (5-bromo-2-chlorophenyl) (2-ethoxyphenyl) methanoneas shown below.

The term “substantially pure” used herein, refers to the purity of desired isomer greater than 99%by HPLC.

The term solvent used herein, refers to the single solvent or mixture of solvents.

Thecontent of undesired isomer of formula (IVA) used herein, refer to less than 1%; preferably less than 0.5%, more preferably less than 0.2%.

In an embodiment, the present invention provides a processfor the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzeneof formula (I) is illustrated in the following synthetic scheme:

In another embodiment, the present invention provides the preparation of substantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone of formula (IV), wherein the compounds of formula (III) is not isolated, which makes present process more economic.

In another embodiment of the present invention, wherein the controlled addition of thionyl chloride was performed by maintaining reaction temperature in a range 20°C to 30°C.

In anotherembodiment of the present invention, wherein the catalyst used in step (a) is selected from N,N-dimethyl formamide, dimethyl sulfoxide, dimethylaminopyridine (DMAP), boron trifluoride etherate, trimethylsilyl chloride or triflateand the like.

In another embodiment of the present invention, wherein the Lewis acid used is selected from aluminium chloride, boron trifluoride etherate, boron trifluoride acetic acid complex (BF3.2CH3COOH), trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper (II) triflate, zinc iodide, hydrochloric acid, toluene sulfonic acid, trifluoroacetic acid, or acetic acid and the like.

In another embodiment of the present invention, wherein the reducing agents is selected from tetramethyldisiloxane (TMDS), triethyl silane, triethylsilyl hydride, tripropylsilane, triisopropylsilane, diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, diisobutylaluminum hydride and the like.

In another embodiment of the present invention, wherein the solvent used is selected from chlorinated solvent such as dichloromethane (DCM), dichloroethane (DCE), chloroform; and alcoholic solvent such as methanol, ethanol, isopropyl alcohol and the like.

In another embodiment of the present invention, wherein controlled addition of Lewis acid is carried at temperature -10°C to 10°C; and a controlled addition of ethoxy benzene or mixture of ethoxy benzene in dichloromethane is carried out at -10°C to 10°C, wherein the reaction temperature plays critical role, which gives better reaction profile in terms of significantly reduced formation of undesired compound and thus to provide good yield and purity of desired compound.

In another embodiment of the present invention, the pH of reaction solution is maintained in 5 to 8using aqueous sodium bicarbonate.

In another embodiment of the present invention, the stripping of resulting compound of formula (IV) is carried out using isopropyl alcohol.

In another embodiment of the present invention, wherein the compound of formula (IV) is used for preparation of compound of formula (I) with or without purification.

In another embodiment of the present invention, wherein the purification of compound (IV) is carried out using simple acid-base purification technique; and solvent used is alcoholic solvent,which is selected from methanol, ethanol, n-butanol and the like.

In another embodiment of the present invention, wherein the acid is selected from hydrochloric acid, acetic acid, sulfuric acid and the like.

In another embodiment of the present invention, wherein the base is selected from
sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and the like.

In another embodiment of the present invention, wherein the purification step is carried out at 0°C to 65°C.

The preparation of the starting materials and reagents used in the present invention are well known in prior art.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXPERIMENTAL
Example 1: Preparation ofsubstantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl)methanone (compound IV)
In a dry RBF (Round bottom flask) under inert atmosphere, dichloromethane(3-5V), 5-bromo-2-chlorobenzoic acid (II, 1.0eq.),N,N-dimethyl formamide (0.01V); were added at 20°C to 30°C. The thionyl chloride (2-3 eq.) was added dropwise at 20°C to 30°Cand reaction mixture was heated at 30°C to 40°C for 1-2 h. The completion of reaction is monitored by HPLC. After completion, the solvent was removed, and stripping given using dichloromethane. To the resulting reaction mixture dichloromethane (4-6 V) added, and aluminium trichloride (1-1.5eq) was added lot-wise at -10°C to 10°C.To the above reaction mixture, a solution of ethoxy benzene (1-1.5eq) in dichloromethane (1-2V) was added dropwise at -10°C to 10°C. The reaction mixture was stirred at -10°C to 10°C for 4-6 h. The completion of reaction is monitored by HPLC. After completion, water was added, and reaction mixture was stirred at 20°C to 30°C for 15-30 min. The organic layer separated,treated with an acid, and pH is maintained at5-8 using aqueous sodium bicarbonate. The solvent was removed under vacuum and reaction mixture was stripped with isopropyl alcohol and obtained the solid compound containing undesired isomer less than 1% by HPLC. Thesolid was optionally purified using methanolat 60°C to 70°C,washed with a cold solution of isopropyl alcohol and methanol. The wet solid was dried to obtain pure compound of formula (IV) with 80-90% yield, 99.5%HPLC purity and the undesired compound is less than 0.2%).

Example 2: Preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene of formula (I).
In a dry RBF, under inert atmospheredichloromethane (4-6V),(5-bromo-2-chlorophenyl) (4-ethoxyphenyl)methanone (IV, 1.0eq.)was addedat 20°C to 30°C. The reaction mixture was cooled to -10°C to 10°Cand tetramethyl disiloxane (1-1.5eq) was added. To above reaction mixture aluminium trichloride was added in lot-wise and after addition reaction mixture was stirred at 10°C to 20°C for 4-6h.The completion of reaction is monitored by HPLC. After completion, water was added slowly to reaction mixture and stirred for 15-20 min. The organic layer separated, treated with an acid-base, and maintained the pH of reaction solution at 5-8 using aqueous sodium bicarbonate.The solvent was removed under vacuum and reaction mixture was stripped with isopropyl alcohol. To above reaction mixture, a solution of isopropyl alcohol and methanol (3-4V) was added and heated at 40°C to 50°C for 1-2h. The reaction mixture was cooled to 20°C to 30°C and seeded with 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene compound. The reaction mixture was cooled to 0°C to 5°C for 1h, solid was filtered and washed with chilled solution of isopropyl alcohol and methanol (0.5-2V). The wet solid was dried to obtain pure compound of formula (I) with90-95% yield, 99.6% HPLC purity.
,CLAIMS:We claim:

1) A substantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone of formula (IV) having purity greater than99%, whereas the corresponding undesired isomer of formula (IVA) is less than 1%.

2) The compound as claimed in claim 1, wherein the substantially pure (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone of formula (IV) is obtained by a process comprising the steps of:
? reacting compound of formula (II) with thionyl chloride, in presence of catalyst; followed by reacting with ethoxy benzene in presence of Lewis acid in solvent to obtain compound of formula (IV).

3) A process for preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene of formula (I) comprising steps of:
a) reacting compound of formula (II) with thionyl chloride, in presence of catalyst; followed by reacting with ethoxy benzene in presence of Lewis acid in solvent to obtain compound of formula (IV),

b) reacting compound of formula (IV) with reducing agent in presence of Lewis acid in solvent to obtain compound of formula (I).

4) The process as claimed in claim 2 or 3, wherein the catalyst is selected from N,N-dimethyl formamide, dimethyl sulfoxide, dimethylamino pyridine (DMAP), boron trifluoride etherate, and trimethylsilyl chloride or triflate.

5) The process as claimed in claim 2 or 3, wherein the Lewis acid is selected from aluminium chloride, boron trifluoride etherate, boron trifluoride acetic acid complex (BF3.2CH3COOH), trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper (II) triflate, zinc iodide, hydrochloric acid, toluene sulfonic acid, trifluoroacetic acid, and acetic acid.

6) The process as claimed in claim 2 or 3, wherein the reducing agents is selected from tetramethyl disiloxane (TMDS), triethyl silane, triethylsilyl hydride, tripropylsilane, triisopropylsilane, diphenyl silane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, and diisobutylaluminum hydride.

7) The process as claimed in claim 2 or 3, wherein the solvent is selected from chlorinated solvent such as dichloromethane (DCM), dichloroethane (DCE), chloroform; and alcoholic solvent such as methanol, ethanol, and isopropyl alcohol.

8) The process as claimed in claim 2 or 3, wherein the addition of thionyl chloride is performed at temperature 20°C to 30°C; addition of Lewis acid and addition of ethoxy benzene is performed at temperature -10°C to 10°C.