FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 4-((2-isopropoxy ethoxy) methyl) phenol compound (I), used as an intermediate in many organic synthesis; particularly a key intermediate for the synthesis of l-[4[2(l-methylethoxy) ethoxy methyl] phenoxy]-3-(l-methylethylamino)-propan-2-ol; commonly known as Bisoprolol or its pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should not be construed as an express or implied admission that such art is widely known or forms part of common general knowledge in the field.
The compound of the present invention namely 4-((2-isopropoxyethoxy)methyl)phenol; hereafter known as compound (I), constitutes a valuable intermediate in the synthesis of numerous therapeutically useful chemical compounds such as Bisoprolol.
Bisoprolol is a broad spectrum responsible for most of the beta-blocking activity and is chemically known as l-[4[2(l-methylethoxy) ethoxy methyl] phenoxy]-3-(l-methylethylamino)-propan-2-ol. Bisoprolol is orally administered and is used in the treatment of angina and hypertension. It is marketed as Fumarate salt under the brand name Zebeta®.

Bisoprolol and/or its pharmaceutical^ acceptable salts are being an important antihypertensive agent; a number of processes for its preparation as well as for its intermediate are known in the art.
US patent No. 4,258,062 describes a process for the synthesis of Bisoprolol using intermediate compound 4-(2-isopropoxyethoxy methyl) phenol (I), wherein the preparation of compound (I) comprises reaction of 4-hydroxybenzyl alcohol (II) with 2-isopropoxyethanol (III). The said reaction requires heating at higher temperature at around 150 °C. However, the process yields the product with higher concentration of impurities because of high reaction temperature. The process described in said patent is illustrated below in Scheme-I.
German patent application No. 44 34 823 describes a process for preparation of 4-(2-isopropoxyethoxy methyl) phenol (I) comprises condensing 4-hydroxybenzyl alcohol (II) with ethylene glycol monoisopropyl ether (III) in the presence of ion exchange resins such as IR 120, Amberlyst 15 and Dowex 50. However, the use of resin involves laborious work such

as its activation. Further, the reaction requires of large quantities of resin and specific design of reactors. The process thus has undesirable features for industrial scale manufacture and hence is not economical.
Indian patent 232665 describes a process for preparation of 4-(2-isopropoxyethoxymethyl) phenol (I) comprises the reaction of 4-hydroxybenzyl alcohol (II) with 2-isopropoxyethanol (III) using sulphuric acid at ambient temperature. However, the use of acid directly in the reaction may increase the formation of impurities. Also, the said process provides a product with poor yield.
Japanese patent application 2000-204055 describes a process for preparation of 4-(2-isopropoxyethoxy methyl) phenol (I) comprising the reaction of 4-hydroxybenzyl alcohol (II) with 2-isopropoxyethanol (III) in the presence of rare earth metal triflate catalyst. In the said process, expensive rare earth metal triflates are used in the process, which are not commercially available. Also, the exemplified process refers the use of column chromatography to obtain the pure product. The use of column chromatography is very tedious and commonly not a preferred method of choice on a commercial scale.
Indian patent 178218 describes a process for preparation of 4-(2-isopropoxyethoxymethyl) phenol (I), comprising the reaction of 4-hydroxybenzyl alcohol (II) with 2-isopropoxyethanol (III) in presence of Amberlite resin. However, the use of resin is not cost effective for commercial scale up.
It is evident from the above discussion of the processes for the synthesis of 4-((2-isopropoxy ethoxy) methyl) phenol (I) described in afore cited patent documents that the reported processes primarily requires adverse reaction conditions, specially designed reactors and expensive reagents. Further, the prior art processes involve additional purification methods such as column chromatography. Also the prior art processes provides product with low yield. In view of these drawbacks, there is a need to develop a simple, commercially advantageous and an industrially viable process for the preparation of 4-((2-isopropoxy ethoxy) methyl) phenol (I) with improved yield and purity.
Inventors of the present invention have developed an improved process that addresses the problems associated with the processes reported in the prior art. The process of the present

invention does not involve use of any additional costly reagents. Moreover, the process does not require additional purification steps and critical workup procedure.
Accordingly, the present invention provides a process for the preparation of a common intermediate used in the synthesis of Bisoprolol namely 4-((2-isopropoxy ethoxy) methyl) phenol (I), which is cost effective, environmentally friendly and commercially scalable for large scale operations.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to an improved process for the preparation of 4-((2-isopropoxyethoxy) methyl) phenol (I), comprising reacting the 4-hydroxybenzyl alcohol (II) with the 2-isopropoxyethanol (III) in the presence of activated silica and in the presence of solvent.
In one aspect, the present invention relates to an improved process for the preparation of 4-((2-isopropoxyethoxy) methyl) phenol (I), comprising reacting the 4-hydroxybenzyl alcohol (II) with the 2-isopropoxyethanol (III) in the presence of activated silica and in the absence of solvent.
In another aspect, the present invention relates to an improved process for the preparation of Bisoprolol or its pharmaceutically acceptable salts, wherein the intermediate 4-((2-isopropoxyethoxy) methyl) phenol (I) is prepared by reaction of 4-hydroxybenzyl alcohol compound (II) with 2-isopropoxyethanol (III) in the presence of activated silica and optionally, in the presence of solvent.
According to another aspect of the present invention, there is provided an improved process for the preparation of 4-((2-isopropoxyethoxy) methyl) phenol (I), wherein the said compound (I) is obtained in a yield of about 85-90%.

DETAILED DESCRD7TION OF THE INVENTION
Accordingly, the present invention relates to an improved process for the preparation of 4-((2-isopropoxyethoxy) methyl) phenol (I), represented by the following formula;
comprising of reacting 4-hydroxybenzyl alcohol (II), represented by the following formula
with the 2-isopropoxyethanol (III) having the following formula
in the presence of activated silica and optionally, in the presence of solvent.
The compound-I obtained by the afore described process is optionally, converted into Bisoprolol free base or a pharmaceutically acceptable salt thereof.
In the context of the present invention, the term "optionally" when used in reference to any element; including a process step e.g. conversion of a compound; it is intended to mean that the subject element is subsequently converted, or alternatively, is not converted to a further compound. Both alternatives are intended to be within the scope of the present invention.
In the context of the present invention, the term "optionally" when used in reference to any element; including a process step e.g. use of solvent; it is intended to mean that the subject

element i.e. solvent is used, or alternatively, solvent is not used during reaction. Both alternatives are intended to be within the scope of the present invention.
In an embodiment, the activated silica used in the process is an acid adsorbed silica.
In an embodiment, the acid used for the activation of silica is selected from but not limited to sulfuric acid, trifiuoroacetic acid, methanesulphonic acid, orthophosphoric acid.
In a specific embodiment, the activated silica is sulfuric acid adsorbed silica.
In an embodiment, the solvent is selected from an aromatic hydrocarbon, a haiogenated hydrocarbon, an alcohol, an ester, an ether, a ketone, a nitrile, an amide* a sulfoxide, a lactam, water; and/or a mixture thereof.
In an embodiment, the solvent is selected from, an aromatic hydrocarbon solvent such as benzene, toluene and xylene; a haiogenated hydrocarbon solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene and chloroform; an alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol and hexanol; an ester solvent such as ethyl acetate, isopropyl acetate and methyl propionate; an ether solvent such as tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether and 1,4-dioxane; an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); a ketone such as acetone; water and/or a mixture thereof.
In a specific embodiment, the solvent is selected from toluene or dichloromethane.
Accordingly, there i§ provided an improved process for the preparation of Bisoprolol or a
pharmaceutically acceptable salt thereof; comprising the steps of:
(1) preparation of 4-((2-isopropoxyethoxy) methyl) phenol (I), represented by the following
formula;

by reacting the 4-hydroxybenzyl alcohol (II), represented by the following formula
with the 2-isopropoxyethanol (III) having the following formula
in the presence of activated silica and optionally, in the presence of solvent.
(2) optionally, converting the compound (I) into Bisoprolol or a pharmaceutically acceptable salt thereof.
In an embodiment, the present invention relates to an improved process for the preparation of 4-((2-isopropoxyethoxy) methyl) phenol (I), comprising reacting the 4-hydroxybenzyl alcohol (II) with the 2-isopropoxyethanol (III) in the presence of activated silica and in absence of solvent.
In a specific embodiment, the process for the preparation of 4-((2-isopropoxyethoxy) methyl) phenol (I) comprises the steps of,
(a) stirring the compound 2-isopropoxyethanol (III) in a reaction flask, and optionally adding solvent,
(b) cooling the reaction mixture of step (a) to a lower temperature of about 5 °C,
(c) adding the activated silica to the reaction mixture of step (b),
(d) adding the compound 4-hydroxybenzyl alcohol (II) to the reaction mixture of step (c),
(e) stirring the reaction mixture of the above step (d) at a temperature ranging from about 25 °C to a higher temperature of about 60 °C.
(f) optionally cooling the reaction mixture of step (e) to ambient temperature, and filtering-off the silica,
(g) treating the reaction mixture of step (f) with an inorganic base,

(h) optionally isolating the product, or carrying forward the reaction mass for further conversion into Bisoprolol without isolation of the product 4-((2-isopropoxyethoxy) methyl) phenol (I).
The process of the present invention as per a specific embodiment is illustrated in the following Scheme-II,
The solvent used in the step-(a) of the above process is selected from, an aromatic hydrocarbon solvent such as benzene, toluene and xylene; a halogenated hydrocarbon solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene and chloroform; an alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol and hexanol; an ester solvent such as ethyl acetate, isopropyl acetate and methyl propionate; an ether solvent such as tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofufan, diethyl ether and 1,4-dioxane; an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); a ketone such as acetone; water and/or a mixture thereof. More preferably, the solvent is selected from toluene or dichloromethane.
The term 'lower temperature of about 5 °C referred to in the step (b) of the above process can range from 0 °C to 10 °C.
The activated silica used in the step (c) of the process is acid adsorbed silica, wherein the acid used for the activation of silica is selected form sulfuric acid, trifluoroacetic acid, methanesulphonic acid or orthophosphoric acid. Preferably, the activated silica is sulfuric acid adsorbed silica.
In an embodiment, in the process of the present invention, the activated silica is used in an amount ranging from ratio of 0.1:1 to 1:1 w/w with respect to compound 4-hydroxybenzyl alcohol (II).

The term "higher temperature of about 25 °C" referred to in the step (e) of the above process can range from 25 °C to 35 °C.
The term "higher temperature of about 60 °C" referred to in the step (e) of the above process can range from 50 °C to 65 °C.
The inorganic base used in the step (g) of the above process is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
The term "isolation of product" at step (h) refers to the chemically known work up methods such as extraction, evaporation, filtration, centrifugation and decantation. The product obtained may be further or additionally dried to achieve the desired moisture values.
In another aspect, the present invention relates to an improved process for the preparation of Bisoprolol or its pharmaceutically acceptable salts, wherein intermediate 4-((2-isopropoxy ethoxy) methyl) phenol (I) is prepared by reaction of 4-hydroxybenzyl alcohol compound (II) with 2-isopropoxyethanol (III) in the presence of activated silica as catalyst and optionally in presence of solvent. Further, the product obtained by the process of the present invention is further converted to Bisoprolol or its pharmaceutically acceptable salt by any of the known prior art methods.
The overall process of the present invention involving preparation of 4-((2-isopropoxy-ethoxy) methyl) phenol (I) and its further conversion into Bisoprolol is illustrated in the following Scheme-Ill:

The process as illustrated in the above Scheme-Ill comprises of optionally dissolving the compound 2-Isopropoxy ethanol (III) in toluene and cooling the reaction mixture to 5 °C. To this cooled reaction mixture was added sulfuric acid adsorbed silica as activated silica followed by addition of 4-hydroxybenzyl alcohol (II) to obtain the corresponding product as 4-((2-isopropoxyethoxy)methyl)phenol (I). The obtained compound (I) is further converted to Bisoprolol using any method reported in the prior art; for instance, the US patent 4,258,062 describes a method wherein the compound 4-((2-isopropoxyethoxy)methyl)phenol (I) is further treated with epichlorohydrin to give 2-[[4-(2-isopropoxyethoxy)fnethyl]-phenoxy-methyljoxirane (IV). The compound (IV) is further reacted with isopropyl amine to give Bisoprolol.
It is evident from the acid catalysed processes for the synthesis of 4-((2-isopropoxyethoxy) methyl)phenol (I) reported in the prior art that the yield of the compound was around 65 % whereas the process of the present invention provided the desired compound, 4-((2-isopropoxyethoxy) methyl)phenol (I) in a yield of about 85-90 %.
In an embodiment, the acid adsorbed silica used in the process of the present invention is prepared by treatment of silica with suitable acid.
In an embodiment, the silica recovered after completion of the reaction of the invention, is reused for the purpose of similar transformations. The silica is separated from the reaction mixture of the present invention by simple filtration method.
The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example-l: Preparation of 4-((2-isopropoxyethoxy) methyl) phenol (I) in the presence of solvent.
A reaction flask was charged with 2-isopropoxyethanol (III) (138.4 ml) and dissolved in toluene (375 ml). The reaction mixture was stirred and cooled to temperature upto 5 °C. The reaction mixture was charged with sulfuric acid adsorbed silica (i.e. H2SO4 activated silica) (75 g) at about 5 °C of temperature. The reaction mixture was further charged with 4-hydroxybenzylalcohol (II) (75 g). The reaction mixture was stirred at ambient temperature and progress of the reaction was monitored by thin layer chromatography (TLC). After completion of reaction; the reaction mass was filtered to recover the silica. The reaction mixture was further treated with potassium carbonate (10 g) and stirred. The reaction mixture was filtered to remove potassium carbonate. The reaction mixture was washed with water (450 ml) and the organic layer was treated with sodium hydroxide solution (21 gm in 325 ml water). The aqueous layer was separated and carried forward for further conversion without isolation of product 4-((2-isopropoxyethoxy) methyl) phenol (I).
Example-2: Preparation of 4-((2-isopropoxyethoxy) methyl) phenol (I) in the absence of solvent.
A reaction flask was charged with 2-isopropoxyethanol (III) (250 ml) and the reaction mixture was cooled to temperature about 5 °C with continuous stirring. The reaction mixture was charged with sulfuric acid adsorbed silica (i.e. H2SO4 activated silica) (20 g) followed by 4-hydroxyben2ylalcohol (II) (20 g). The reaction mixture Was stirred at ambient temperature for about 24 hours. The reaction mass was filtered to recover the silica. To the reaction mixture, potassium carbonate (10 g) was added and the reaction mixture was stirred for one hour. The reaction mixture was filtered to remove potassium carbonate. The reaction mixture was partitioned between toluene (60 ml) and water (60 ml) to yield 29.9 g of the title product with 87 % of yield.
Example-3: Preparation of 4-((2-isopropoxyethoxy) methyl) phenol (I) in the absence of solvent.

A reaction flask was charged with 2-isopropoxyethanol (III) (250 ml) and the reaction mixture was cooled to temperature about 5 °C with continuous stirring. The reaction mixture was charged with sulfuric acid adsorbed silica (i.e. H2SO4 activated silica) (20 g) followed by 4-hydroxybenzylalcohol (II) (20 g). The reaction mixture was stirred at ambient temperature and the progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mass was filtered to recover the silica. To the reaction mixture, potassium carbonate (10 g) was added and the reaction mixture was stirred for one hour. The reaction mixture was filtered to remove potassium carbonate. The reaction mixture was partitioned between toluene (60 ml) and water (120 ml), to which sodium hydroxide solution (5.6 g in 87 ml water) was added. The aqueous layer was separated and carried forward for further conversion without isolation of product 4-((2-isopropoxyethoxy) methyl) phenol (I).
Example-4: preparation of sulfuric acid adsorbed silica (H2SO4 activated silica)
A reaction flask Was charged with silica (20 g) and acetone (60 ml) at temperature about 25 °C. To this stirring reaction mixture was added concentrated sulfuric acid (13 ml) and stirred for one hour at a temperature of about 25 °C. The solvent was removed completely by vacuum distillation to yield dry H2SO4 activated silica.
Example-5: Preparation of 4-((2-isopropoxyethoxy) methyl) phenol (I) in the absence of solvent.
A reaction flask was charged with 2-isopropoxyethanol (III) (250 ml) and the reaction mixture was cooled to temperature about 5 °C with continuous stirring. The reaction mixture was charged with sulfuric acid adsorbed silica (i.e. H2SO4 activated silica) (20 g) followed by 4-hydroxybenzylalcohol (II) (20 g). The reaction mixture was stirred at ambient temperature for about 24 hours. The reaction mass was filtered to recover the silica. To the reaction mixture, potassium carbonate (10 g) was added and the reaction mixture was stirred for one hour. The reaction mixture was filtered to remove potassium carbonate. The reaction mixture was partitioned between toluene (60 ml) and water (60 ml) to yield 25.5 g of the title product with 75 % of yield.

We claim:
A process for the preparation of 4-((2-isopropoxyethoxy) methyl) phenol (I), of the following formula;
comprising, reacting 4-hydroxybenzyl alcohol (II), of following formula
with 2-isopropoxyethanol (III) of following formula
in the presence of activated silica and optionally, in the presence of solvent.
The process according to claim 1, wherein the activated silica is an acid adsorbed
silica.
The process according to claim 1 and claim 2, wherein the acid is selected from
sulfuric acid, trifluoroacetic acid, methanesulphonic acid or orthophosphoric acid.

4. The process according to claim 1, wherein the activated silica is used in an amount ranging from ratio of 0.1:1 to 1:1 w/w with respect to the compound, 4-hydroxy benzyl alcohol (II).
5. A process for the preparation of 4-((2-isopropoxyethoxy) methyl) phenol (I), of the following formula;
comprising, reacting the 4-hydroxybenzyl alcohol (II), of following formula
with the 2-isopropoxyethanol (III) of following formula
in the presence of sulfuric acid adsorbed silica (i.e. H2SO4 activated silica) and optionally, in the presence of solvent.
The process according to claim 1 or claim 5, wherein the solvent is selected from an aromatic hydrocarbon, a halogenated hydrocarbon, an alcohol, an ester, an ether, a ketone, a nitrile, an amide, a sulfoxide, a lactam, water; and/or a mixture thereof. The process according to claim 1 or claim 5, wherein the solvent is selected from toluene or dichloromethane.
The process according to claim 1 or claim 5, wherein the compound (I) is further converted into Bisoprolol free base or a pharmaceutically acceptable salt thereof.

The process according to claim 1 or claim 5, wherein the compound (I) is obtained in a yield of about 85-90 %.