Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF 4-(2-ISOPROPOXYETHOXYMETHYL)PHENOL
Abstract	The present invention relates to a process for the preparation of 4-(25-isopropoxyethoxy-methyl)phenol of Formula I Which is an important intermediate in the preparation of an antihypertensive drug Bisoprolol of Formula II

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FIELD OF THE INVENTION The present invention relates to an industrially advantageous and an improved process for the preparation of 4-hydroxybenzylalkyl ethers. More specifically, the present invention relates to a process for the preparation of 4-{2-isopropoxyethoxyn]ethyI)-phenol of Formula I BACKGROUND OF THE INVENTION Bisoprolol of Formula II, is a Pi-selective adrenoceptor blocking agent and is chemically known as l-[4-[[2-(l-methylethoxy)ethoxy]methyl]phenoxy]-3-[(l-methylethyl)amino]-2-propanol. Bisoprolol is orally administered and is used in the treatment of angina and hypertension. 4-(2-Isopropoxyethoxymethyl)phenol of Formula I is the key intermediate in the preparation of Bisoprolol US patent 4,258,062 has described the synthesis of Bisoprolol using 4-(2-isopropoxyethoxymethyl)phenot as the starling material, in this patent 4-(2- -2- IsopropQxyethoxymethyl)phenol of Formula I has been prepared by healing 4-hydroxybenzyl alcohol of Formula I!!, However, in this process due to heating at higher temperature impurities are forming which is not desirable for preparing pure bisoprolol. German patent application DE 44 34 823 discloses a process for the preparation of 4-(2-isopropoxyethoxymethyl)phenol by condensing 4-hydroxybenzyi alcohol with ethylene glycol monoisopropyl ether in the presence of ion exchange resins such as IR 120, Amberlyst 15, Dowex 50 etc. But the use of resin involves laborious work such as its activation, requirement of large quantities of resin and specific design of reactors. The process thus have undesirable features for industrial scale manufacture and is not economical. Chem. Pharm. Bull., 2002, 50(3), 380-382 discloses a method for the preparation of 4-(2-isopropoxyeihoxymethyl)phenol, which comprises the reaction of 4-hydroxybenzyl alcohol with 2-isopropoxyethanol in the presence of rare earth metal triflates. But in this process polymerization occurs possibly due to heating at higher temperature. Further, expensive rare earth metal triflates are used in this process, which are not commercially available. However, in the exemplified process, column chromatography was used to obtain the pure product. The use of column chromatography is very tedious, cumbersome and generally not a preferred method of choice on a commercial scale. For the above said reasons this method is not viable for commercial purpose. -3- in view of the above, there is an urgent need to develop an efficient and simple method to prepare 4-(2-isopropoxyethoxymethyl)phenol, which should be simple to operate on commercial scale. Therefore, it is an object of the present invention to provide a simple, efficient and commercially viable process for the preparation of 4-(2-isopropoxyethoxy methyl)-phenol of Formula !, wherein use of ion exchange resins and other expensive reagents is avoided. SUMMARY OF THE INVENTION: The present invention relates to a process for the preparation of 4-(2-isopropoxyethoxy-methyi)phenol of Formula I, using acid as catalyst either in the presence or absence of solvent, at a temperature 0 to !00X, - isolating 4-(2-isopropoxyethoxymethyl)phenol by conventional methods. -4- Further the compound of Formula i is converted to Bisoprolol, by reacting it with epichlorohydrin and treating the resulting product with isopropyl amine. It may optionally be converted to a pharmaceutically acceptable salt. DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention relates to an improved process for the preparation of 'H2-isopropoxyethoxymethyl)phenol of Formula I from 4-hydroxybenzyl alcohol of Formula III and isopropoxyalcohol of Formula IV, using acid in catalytic amount In the presence or absence of solvent. The acid used can be organic acid or inorganic acid such as sulfonic acids for example p-toluenesulfonic acid, melhanesulfonic acid, benzenesulfonic acid, naphthalanesuIfonic acid; halo acids such as hydrochloric acid, hydrobromic acid; sulfuric acid, phosphoric acid, and the like or mixture thereof, preferred being sulfonic acids and most preferred being p-toluenesulfonic acid. The amount of catalyst plays an important role on the rate of the reaction. If amount of catalyst is increased the reaction is faster. The catalyst can be used in an amount of 2-10 % to the weight of the 4-hydroxyben2yl alcohol, preferably in an amount of 1-5 %. The solvent used in the present condensation reaction can be selected from hydrocarbons, halogenated hydrocarbons, ethers, ketones, nitriles, amides, sulfoxides and the like or mixtures thereof. In one of the embodiments of the present invention the reaction is carried out in the absence of solvent. Usually, condensation reaction is carried out at a temperature between 0 to 100°C and preferably 10 to 40°C and most preferably the reaction is carried out at 15 to 30°C -5- When the reaction is carried out in the absence of solvent, on completion of reaction, the reaclion mass is diluted with the inert solvent exemplified above and neutralized with a base or washed with water until the pH of the washings is 4.5-7.0 and preferably between 5.0- 5.8. When the reaction is conducted in the presence of solvent, after completion of reaction, the organic layer is washed with water or base until the pH of the washings is 4.5-7.0 and preferably 5.0- 5.8. This washing is essential to remove any traces of acid, which if present, leads to degradation during Isolation of product. The bases, which can be used, are dilute aqueous solutions of alkali metal hydro.xides, bicarbonates, carbonates or aqueous ammonium hydroxide solution. Thereafter, the organic layer is concentrated and crude product obtained is purified by distillation under reduced pressure to obtain the compound of Formula I in high yield and having purity greater than 98 % by HPLC. The compound of Formula 1 is isolated and converted to Bisoprolol by the method which comprises, - reacting compound of Formula I with epichlorohydrin m the presence of a base, such as sodium hydroxide or potassium hydroxide at a temperature of 30-60°C to prepare epoxy benzyl ether of Formula V, -6- - treating epoxy benzyl ether of Formula V with isopropyi amine in hydroxylated solvents such as by the method reported in the prior art. Specifically the reaction is conducted in alcohols such as ethano), methanol, isopropyi alcohol, and the like, to prepare Bisoproloi of high purity. Bisoprolol thus prepared is further converted to its fumarate salt by treating with fumaric acid. Major advantages realized in the present invention are the use of catalytic amount of acid under mild conditions, to prepare 4-(2-isopropoxyethoxymethyl)phenol of Formula I in high yield and purity without using any ion exchange resin and expensive reagents. Further the invention is more fully described with reference to the following examples, which are only illustrative and not to be construed as any limitation thereof: EXAMPLE 1 PREPARATION OF 4-(2-ISOPROPOXYETHOXYMETHYL) PHENOL To a mixture of 4-hydroxybenzyl alcohol (lOQ g, 0.80 mol) and 2-isopropoxyethanol {541.8 g, 5.2 moi) was added /7-toluenesulfonic acid monohydrate (2 g, 2% w/w ) at 25-30°C. The reaction mass was stirred at 25-30°C until unreacted 4-hydroxybenzyl alcohol is EXAMPLE 2 PREPARATION OF 4-{2-ISOPROPOXYETHOXYMETHYL) PHENOL 4-Hydroxybenzyl alcohol (100 g, 0.80 mol) was added to 2-isopropoxyethanoi (36Ig, 3.47 mol) and then added p-toluenesulfonic acid monohydrate (2 g, 2% \w/w). The reaction was continued till urireacted 4-hydroxybenzyI alcohol was 2.6% as evidenced by HPLC analysis. After completion of reaction, the product was extracted in methylene chloride (700 ml) and washed the reaction mass with DM water, till pH of final washing was 5.66, The solvent and unreacted 2-isopropoxyethanol were distilled under reduced pressure to obtain 142 g of crude product, which was purified by distillation under reduced pressure (b.p. MO-ISCC/O.S mm) to yield pure title product having purity 95.18% by HPLC. EXAMPLE 3 PREPARATION OF 4-(2-ISOPROPOXYETHOXyMETHYL) PHENOL 4-Hydro);ybenzyI alcohol (10 g, 0.08 mol) was added to 2-isopropQxyethanol (54.18 g, 0.52 mol), followed by />-toluenesulfonic acid monohydrate (0.5 g, 5% w/w) at 25-30'C. Reaction mass was stirred at ambient temperature and monitored by qualitative HPLC analysis. After 5.5 h, when unreacted 4-hydroxybenzyl alcohol on qualitative HPLC was 1.7%, added 50 ml of methylene chloride and washed the reaction mass with DM water (2x50 ml). Distilled out methylene chloride and unreacted 2-isopropoxyethanol under reduced pressure (500-5 mm Hg) / 30-55°C, to get 16.5 g of crude product with a purity of 86.33%, which was further purified to get 13.54 g of pure product having purity 98.91% by HPLC. EXAMPLE 4 PREPARATION OF 4-(2-ISOPROPOXYETHOXVMETHYL) PHENOL Methanesulphotiic acid (0.1 g, 2%w/w) was added to a mixture of 4-hydroxybenzyl alcohol (5 g, 0.04 mo!) and of 2-isopropoxyethanol (27.09 g, 0.26 mol) and the reaction mass was stirred at ambient temperature. After completion of reaction the reaction was worked up in a similar manner as given in Example 1, to yield 5.9 g of the title compound. EXAMPLE 5 PREPARATrON OF 4-(2-lSOPROPOXYETHOXYMETHVL) PHENOL To a mixture of 4-hydroxybenzyl alcohol (5 g, 0.04 mol) and of 2-isopropoxyethanol (27.09 g, 0.26 mol), sulfuric acid {0.1 g, 2 % w/w) was added and the reaction mass was stirred at ambient temperature. After completion of the reaction, the reaction was worked up in a similar manner as given in Example 1, to yield 5.7 g of the title compound. EXAMPLE 6 PREPARATION OF 4-(2-ISOPROPOXYETHOXYMETHYL) PHENOL To a mixture of 4-hydrosybenzyl alcohol (5 g, 0.04 mol) ^d of 2-isopropoxyethanol (27.09 g, 0.26 mol) was added 35% w/w hydrochloric acid (O.i g, 2% w/w) and stirred the reaction mass at ambient temperature. After completion of the reaction, the reaction mass was worked up in similar manner as given in Example 1, lo yield 4.1g of the title compound. / EXAMPLE 7 PREPARATION OF 4-(2-ISOPROPOXVETHOXYMETHYL) PHENOL Phosphoric acid (0.1 g, 2% w/w) was added to a mixture of 4-hydroxybenz>'l alcohol (5 g, 0.04 mol) and of 2-isopropoxyethanoI (27.09 g, 0.26 mol) and stirred at ambient temperature. After completion of the reaction, the reaction mass was worked up in a similar manner as given in Example 1, to yield 5.8 g of the title compound EXAMPLE 8 PREPARATION OF 4-(2-ISOPROPOXYETHOXyMETHYL) PHENOL 4-Hydroxybenzyl alcohol (5 g, 0.04 mol) and 2-isopropoxyethanol (9.03 g, 0.08 mol) were taken in 25 ml of tetrahydrofuran, and to this mixture was added/?-toluenesulfonic acid monohydrate (1 g, 2% w/w), The reaction mass was stirred at ambient temperature and after completion of the reaction, reaction mass was washed with DM water (25 ml) to remove/i-toluenesulfonic acid. The organic layer was concentrated to obtain 7.75 g of crude product, which was purified in a similar manner as given in Example 1. EXAMPLE 9 PREPARATION OF BISOPROLOL FUMARATE Stepl PREPARATION OF 2-||4-ISOPROPOXYETHOXY]PHENOXYMETHYL]OXIRANE ( Epoxy Benzyl Ether ) To a mixture of 4-(2-isopropoxyethoxymethyl)phenol (30 g, 0.14 mol) in 120 ml epichlorohyddn, sodium hydroxide (5.99 g, 0.15 mol) was added and stirred at 40-45°C -10- After completion of the reaction, which is monitored by HPLC, the reaction mixture was cooled to 30-35°C and diluted with DM water (250 ml). The product was extracted with ethyl acetate (2x250ml) and the combined ethyl acetate extracts were washed with DM water (1x30 ml). The organic layer was concentrated at 40-60°C under reduced pressure to obtain 37.5 g of the title compound having 84.45% purity by HPLC. Step 2 PREPARATION OF BISOPROLOL 2-[[4-Isopropoxyethoxy]phenoxymethyl]oxirane (30 g, 0.11 mol) was dissolved In 60 ml of ethanol, cooled to I0-I5°C and to this isopropyiamine (45 ml) was added slowly in 30 minutes at I0-[5°C. The reaction mass was stirred at lO-IS'^C and monitored by qualitative HPLC analysis. After completion of reaction, excess of isopropyiamine / ethanol was removed from reaction mass at 35-45°C under reduced pressure- To the residue, ethyl acetate (90 ml) was added and washed with DM water (2x30 ml). To the ethyl acetate layer, DM water (90 ml) was added and pH was adjusted to 1.2-1.3 using 35% w/w hydrochloric acid (10 ml). The layer were separated and to the aqueous layer, aqueous ammonia (17% w/w) was added till the pH between 9.8-9.9 was achieved. Thereafter, the reaction mixture was extracted with ethyl acetate (2x50 ml) and the combined organic layer was washed with DM water (1x50 ml) at 30°C. The organic layer was concentrated at 40-60°C under reduced pressure to obtain 29.83 g of the title compound having 93.69% purity by HPLC. Step 3 PREPARATION OF BISOPROLOL FUMARATE A mixture of ethyl acetate (64 ml) and methanol (4 ml) was added to the Bisoprolol base (20 g, 0.06 mol) and heated the reaction mass to 50°C. To this fumaric acid (3.56 - U- g, 0.03 mol) was added and stirred the reaction mass at 50°C, till the clear solution was obtained. The reaction mass was cooled slowly to 20'C and was stirred for 3 hrs to complete the crystallization. Product was filtered, washed with chilled ethyl acetate (2x20 ml) and dried at 50-55°C under reduced pressure to obtain 20 g of the title compound. - 12- WE CLAIM: 1. A process for the preparation of 4-(2-isopropoxyethoxymethyl)phenol of Formula I, using acid as catalyst either in the presence or absence of solvent, at a temperature 0 to 100°C, - isolating 4-(2-isopropoxyethoxymethyI)phenol by conventional methods. 2. The process according to claim I, wherein the acid used is organic acid or inorganic acid. 3. The process according to claim 2, wherein the organic acid or inorganic acid is selected from sulfonic acids for example p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; phosphoric acid, halo acids such as hydrochloric acid, hydrobromic acid; sulfuric acid or mixtures thereof. - 13- 4. The process according to claim 3, wherein the preferred acid is p-toluenesulfonic acid. 5. The process according to claim 1, wherein the acid is used in the amount of 2-10 % to the weight of the 4-hydroxybenzyl alcohol, preferably In the amount of 1-5 %. 6. The process according to claim 1, wherein the solvent is selected from hydrocarbons, halogenated hydrocarbons, ethers, ketones, nitrites, amides, sulfoxides or mixture thereof 7. The process according to claim 6, wherein the preferred solvents are tetrahydrofuran, methylene chloride, toluene. 8. The process according to claim 1, wherein the reaction is carried out preferably at a temperature of 10 to 40°C and most preferably at 15 to 30°C. 9. The process according to claim 1, wherein the washing is carried out with water or dilute aqueous solutions of alkali metal hydroxides, bicarbonaies, carbonates or aqueous ammonium hydroxide solution. 10. The process according to claim 1, wherein the compound of formula I is converted to Bisoprolol of formula II, through a compound of Formula V, - converting to the pharmaceutical ly acceptable salt by treating with fumaric acid using conventional methods.

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