Title of Invention	A PROCESS FOR THE PREPARATION 3-SUBSTITUTED-1, 2-DIHYDROXYBENZENE, 2-SUBSTITUTED-1, 4-DIHYDROXYBENZENE AND THEIR DERIVATIVES THEREOF
Abstract	A process for the preparation of componds of formula 1 and II. Wherein R represents hydrogen atom or a hlogen selected from F or Cl or Br, or No2, wherein R1 and R2 represent hydrogen or a C1-C4 alky1, substituted and unsubstituted slky1, aralky1, heteroalkyl groups, wherein R1 and R2 are idetical or different, said process comprising the steps of; reacting 2-subtituted phenol wiht an ally1 halide and a solvent to obtain a substituted ally1 pheny1 ether; rearranging the ally1 pheny1 ether to obtain an isomeric pheno1 mixture; alkylating the isomeric pheno1 mixture wiht an alkylating agent; separating the isomeric compounds to obtain ally1 compounds; isomerising the ally1 compounds to obtain propeny1 benzene derivatives to corresponding benzaldehydes; oxidizing further the benzaldehydes to obtain corresponding phenols; alkylating the phenols to ontain corresponding dialkoxybenzenes; and dealkylating the dialkoxybenzenes to obtain corresponding dihydroxy benzenes of formula 1 and II and their derivatives in good yield.

Title of Invention

A PROCESS FOR THE PREPARATION 3-SUBSTITUTED-1, 2-DIHYDROXYBENZENE, 2-SUBSTITUTED-1, 4-DIHYDROXYBENZENE AND THEIR DERIVATIVES THEREOF

Abstract

A process for the preparation of componds of formula 1 and II. Wherein R represents hydrogen atom or a hlogen selected from F or Cl or Br, or No2, wherein R1 and R2 represent hydrogen or a C1-C4 alky1, substituted and unsubstituted slky1, aralky1, heteroalkyl groups, wherein R1 and R2 are idetical or different, said process comprising the steps of; reacting 2-subtituted phenol wiht an ally1 halide and a solvent to obtain a substituted ally1 pheny1 ether; rearranging the ally1 pheny1 ether to obtain an isomeric pheno1 mixture; alkylating the isomeric pheno1 mixture wiht an alkylating agent; separating the isomeric compounds to obtain ally1 compounds; isomerising the ally1 compounds to obtain propeny1 benzene derivatives to corresponding benzaldehydes; oxidizing further the benzaldehydes to obtain corresponding phenols; alkylating the phenols to ontain corresponding dialkoxybenzenes; and dealkylating the dialkoxybenzenes to obtain corresponding dihydroxy benzenes of formula 1 and II and their derivatives in good yield.

Full Text	FORM 2 THE PATENTS ACT 1970 (39 of 1970) & The Patent Rules 2005 COMPLETE SPECIFICATION , (see sections 10 & rule 13) 1. TITLE OF THE INVENTION “A PROCESS FOR THE PREPARATION 3-SUBSTITUTED-l, 2-DIHYDROXYBENZENE, 2-SUBSTITUTED-l, 4-DIHYDROXY BENZENE AND THEIR DERIVATIVES THEREOF” 2. APPLICANT (S) NAME I NATIONALITY I ADDRESS HIKAL LIMITED AN INDIAN COMPANY 32/1, Kalena Agrahara, Banneraghatta Road, BANGALORE 560 076 3. PREAMBLE TO THE DESCRIPTION COMPLETE SPECIFICATION The following specification particularly describes the invention and the manner in which it is to be performed. A PROCESS FOR THE PREPARATION OF 3-SUBSTITUTED-l, 2-DIHYDROXYBENZENE, 2-SUBSTITUTED-l, 4-DIHYDROXY BENZENE AND THEIR DERIVATIVES THEREOF Field of the invention The present invention relates to process for the preparation of 3 -substituted- 1,2-dihydroxybenzene (I), 2-substituted-1, 4-dihydroxybenzene (II) and their symmetric and unsymmetrical O-alkyl, aralkyl, substituted and unsubstituted alkyl or aralkyl derivatives from 2-substituted phenols and an allyl halide. Background of the invention 1, 2-dihydroxybenzenes i.e., catechols exhibit a variety of molecular modes of action in biological Systems and have attracted the attention of the pharmaceutical industry. Among the catechols in general, catechols that have a substituent on 3-position are of particular interest. 3-fluorocatechol and its alkoxy derivatives are potential precursors in the synthesis of a wide range of Pharmaceuticals such as adrenergic catecholamine, biogenic amines and the recent 2-iminopyrrolidine derivatives as thrombin receptor antagonists. Few methods are available which either give a very poor to moderate yield or unselective methods utilizing 2-substituted phenol particularly 2-fluorophenol as a key starting material. They also involve elaborative approach, much expensive, raw materials, and use of expensive organometallic reagents, which lead to problems with handling, safety, and waste disposal. Some of the methods also involve troublesome laborious biochemical approach giving very poor yield and difficulty in scale-up for large-scale industrial production. For example, Hansen et al., (Tetrahedron Lett 46, 2005, 3357-3358) have reported a surprising yield of 66 % for 3-fluorocatechol employing a typical procedure reported for 3-bromocatechol, Which involves magnesium chloride, para formaldehyde, triethyl amine base and tetrahydrofuran solvent in an atmosphere of Argon. According to their procedure, insitu oxidation of the expected 3-fluorosalicylaldehyde gives 3-fluorocatechol. Lynch et al., (J. Biotechnol, 58,1997, 167-175) have disclosed the preparation of 3-fluorocatechol from fluorobenzene by utilizing pseudomonas putida ML2 biocatalyst. This method involves a longer reaction time, huge reaction mass volume and as a whole is laborious and the yield is rather poor for industrial scale-up. Finkelstein et al., (Applied and Environmental Microbiology, Vol.66, 2000, 2148-2153) have described the preparation of 3-fluorocatechol from 2-fluorophenol by a biochemical transformation. Again this method is low yielding, troublesome, time consuming and doesn't fit for large scale industrial production. Other workers like Martan et al. in US 4124643 have disclosed a method for preparing 2-allyl-6-fluorophenol with only 88% conversion of 2-fluorophenol employing allyl chloride as other starting material. In their art, the reaction is not completed and involves purification of the product by vacuum distillation resulting in only 76.6 % molar yield. In the next stage, the process involved Claisen’s type rearrangement of allyl-2-fluorophenylether in the presence of t-butylhydroxyanisole as an antioxidant and sodium carbonate as a base catalyst under nitrogen atmosphere. The disadvantage of this step is that it gives low yield and involves distillation procedures. Ladd et al. (Synth. Commun., 15(1), 1985, 61-69) have reported a process for producing 1-fluoro-2, 3-dimethoxybenzene (8, R=F, R1=R2=CH3) starting from 2-fluorophenol (1, R=F) and allyl bromide. In their method the first step involves extraction of the product with ether solvent after quenching the cooled reaction mass with water. The disadvantage of this method is that it is expensive, involves unnecessary extraction of the product with a solvent and distillation of the product leading to 85 % molar yield only. The overall yield of the targeted product is only about 40%. Recently, Suzuki et al. in US 20050004204, have disclosed a process for preparing 1, 2-diethoxy-3-fluorobenzene (8, R=F, R1= R2=C2H5) starting from expensive 3-fluorocatechol (8, R=F, R1= R2=H) and ethyl iodide utilizing dimethyl formamide as solvent. The disadvantage of this process is that it is expensive, low yielding and involves purification of product by column chromatography. The novel and inventive feature of the present invention is that it involves a new sequence for producing potential precursors for a wide range of modern pharmaceutical ingredients with high yield and purity, which has never discussed before for small scale or large scale industrial productions. Objects of the present invention It is therefore the primary object of this invention to provide an improved and efficient process for the preparation of 3-substituted-l,2-dihydroxybenzene (I), 2-substituted-l, 4-dihydroxybenzene (II) and their symmetric and unsymmetrical O-alkyl, aralkyl, substituted and unsubstituted alkyl or aralkyl derivatives from 2-substituted phenols and an allyl halide. An object of the present invention is to provide a process for the production of the substituted dihydroxy benzene compounds and their derivatives that is cost effective and doesn't generate a significant amount of unwanted/ unrecoverable waste or byproduct. Another object of the present invention is to provide a process for the production of the substituted dihydroxy benzene compounds and their derivatives in high yields and quality without extensive purifications, special equipments or extra set-up in industries. Still another object of the present invention is to provide a process for the production of the substituted dihydroxy benzene compounds and their derivatives for industrial scale up. Further object of the present invention is to provide a process for the production of substituted dihydroxy benzene compounds and their derivatives by providing a safe handling method which does not use expensive organometallics, troublesome approach towards work up, isolation and purification of intermediates and products. Yet another object of the present invention to provide a process for the production of substituted dihydroxy benzene compounds and their derivatives which does not involve waste disposal problems. Summary of the present invention Accordingly, the present invention relates to a process for the preparation of 3-substituted-l, 2- dihydroxybenzene (I), 2-substituted-l, 4-dihydroxybenzene (II) and their derivatives thereof in a series of steps. wherein R represents hydrogen atom or a halogen selected from F or Cl or Br, or NO2, wherein R1 and R2 represent hydrogen or a C1-C4 alkyl, substituted and unsubstituted alkyl, aralkyl, heteroalkyl groups, wherein R1and R2 are identical or different, said process comprising the steps of; reacting 2-substituted phenol with an allyl halide in the presence of a base of reduced particle size and a solvent to obtain a substituted allyl phenyl ether; rearranging the allyl phenyl ether in the presence of a suitable solvent to obtain an isomeric phenol mixture; alkylating the isomeric phenol mixture with a suitable base, a ketonic solvent and an alkylating agent; separating the isomeric compounds by fractional distillation to obtain allyl compounds; isomerising the allyl compounds in the presence of a metallic hydroxide and an alcoholic solvent to obtain crude propenyl benzene derivatives; diluting the crude propenyl benzene derivatives with water and neutralizing with mineral acid to obtain aqueous filtrate of propenyl benzene derivatives followed by the isolation of propenyl benzene derivatives in the presence of a suitable solvent, oxidizing the aqueous filtrate of neutralized propenyl benzene derivatives to corresponding benzaldehydes in the presence of oxidants, a halo hydrocarbon solvent and a phase transfer catalyst; oxidizing further the benzaldehydes with a suitable peroxide in a halo hydrocarbon solvent to obtain corresponding phenols; alkylating the phenols with a suitable base, solvent and an alkylating agent to obtain corresponding dialkoxybenzenes; and dealkylating the dialkoxybenzenes in the presence of an acid to obtain corresponding dihydroxy benzenes of formula I & II and their symmetric and unsymmetrical O-alkyl, aralkyl, substituted and unsubstituted alkyl or aralkyl derivatives in quantitative yield and with high purity. Detailed description of the of the present invention Accordingly, the present invention provides a process for producing 3-substituted-1, 2-dihydroxybenzene (I), 2~substituted-l, 4-dihydroxybenzene (II) and their alkyl derivatives and more particularly 3-substituted catechol (8, R1= R2 =H) and its methyl and ethyl derivatives of the following structural formulae, whereby greater yields of the desired products are obtained. > 11 wherein R represents hydrogen atom or a halogen selected from F or Cl or Br, or NO2, wherein R1 and R2 represent hydrogen or a C1-C4 alkyl, substituted and unsubstituted alkyl, aralkyl, heteroalkyl groups, wherein R1 and R2 are identical or different. The reaction scheme of the present process is as follows: SCHEME i : Allyl halide, acetone, K2CO35 ~60 °C, 4-5 hrs. ii : Heat, N-methyl pyrrolidinone, ~ 195 °C, 5-6 hrs. iii, vii : Alkylating agent, Acetone, K2CO3, heat, ~ 60 °C, 5-6 hrs. iv : KOH / methanol, heat, 60-70 °C, 24 hrs. v : KMnCV Methylenedichloride, Benzyl triethyl ammonium chloride, 0-5 °C, 1-2 hrs. vi : m-Chloroperbenzoic acid/Methylenedichloride, or H2O2/ HCO2H, 35-40 °C, 24 hrs. The first step of the present invention comprises heating 2-substituted phenol(l) with a suitable basic material in presence of an organic solvent under stirring and dropping a suitable allyl halide in to the reaction vessel over a period of 4-5 hr. The reaction is carried out with in a temperature range of about 25° to 110°C, preferably between about 25° to 80°C and most preferably between about 50° to 70°C. Allyl halides used are allyl chloride, allyl bromide, allyl iodide, and the like in an amount of 1-4 mole % and the preferred halide quantity is 1-2,5 mole %. The basic material includes a basic metal carbonate or hydroxide. For example, basic or alkaline reagents which may be used comprise sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, magnesium carbonate, cesium carbonate and the like in an amount of 1-4 mole %. Potassium carbonate is the usually preferred reagent, which is free of water of crystallization and Which has to be brought to a fine particle size by milling, for example in ball mills or pinned-disk mills. Potassium carbonate having fine particle fraction of 85% or smaller than 0.1 mm and 70 % or smaller than 0.05 mm is practically suitable. While the organic solvents used are acetone, methylethylketone, dipropylketone, methylpropylketone, hydrocarbon solvents such as hexanes, heptanes, cyclohexane, and the like in a 2-15 times by volume per mole of phenol compound used. Reaction may be carried out at atmospheric pressure or super atmospheric pressure ranging from about 1 to 50 atmospheres is used for the reaction. Time that is needed for addition of allyl halide into a reaction flask of 2-substituted phenol may be approximately in the range of about Ihr to 4 hrs, preferably addition time is in the range of about 1.5 to 2.5 hrs. After completion of the “eaction, the reaction mass is concentrated, cooled and quenched as such with water. The layers are illowed to separate for about 0.5 to Ihr. The separated organic layer is given water wash and dried )n a suitable drying agent such as anhydrous sodium sulphate, anhydrous magnesium sulphate and he like. The amount of water used for quenching the reaction mass be about 4-15 times based on he weight of the phenol used for the reaction. Thereafter, the crude ortho substituted allyl phenyl ether (2) which is thus obtained is heated to 180-225 °C quickly in a suitable solvent to effect a Claisen's type rearrangement for a time period of about 2.5 hrs to 12 hrs in an atmosphere of nitrogen, preferably at about 195° to 205°C. The solvents used comprise N-methyl pyrrolidinone, diphenyl ether, decaline, N,N-diethylaniline, and the like and preferably N-methyl pyrrolidinone, since it is easily removed from the product by washing with water. The amount of solvent used is about 0.75 to 4.0 volumes based on the weight of the allyl phenyl ether used for the rearrangement and preferably in the range 1.5 to 2.5 volumes of the solvent. After completion of rearrangement reaction, the reaction mass is cooled and quenched with water. The layers are allowed to separate during a period of about 0.5 to Ihr and the separated organic layer is given brine wash in a volume of 1: 2 ratio based on the weight of starting material used. The aqueous layer is extracted with a suitable halohydrocarbon solvent such as dichloromethane, chloroform, dichloroethane and the like, in an amount of approximately 1-3 volumes of the solvent based on the weight of the starting material used. Washing the organic extract with water and removing the solvent by distillation may offer about 2-5 % of the additional product, which is added to the main organic layer. The thus formed crude 2-allyl-6-substituted phenol (3) and 4~allyl-2-substituted phenol (3a) mixture is alkylated without further purification with an alkylating agent, utilizing a basic material and a solvent. The alkylating agent is selected from the group of methyl and ethyl esters of sulphuric acid, alkyl halides such as methyl iodide, ethyl iodide, ethyl bromide, propyl bromide propyl iodide, isopropyl bromide, butyl bromide and the like, in an amount of about 1 to 10 mole % based on the total weight of the isomeric phenol mixture and considering 1:1 yield ratio from the previous step reaction. The solvents, basic materials employed including their quantities and particle size, temperature of the reaction are the same as mentioned above for allylation of 2-substituted phenols (1). After completion of the reaction, the reaction mass is cooled to about 15-35°C, preferably about 25-30°C, quenched with water in 3-10 volumes based on the weight of the starting material used and the layers are separated. The organic layer is washed with brine or water (5-10 % by volume based on the weight of the starting compound) to remove the adhered inorganics and trace of the used solvent. The mixture of crude ortho allyl product (4) and para allyl product (4a) is taken to the subsequent isomerization step or separated almost completely by fractional distillation technique. The ideal and most advantageous method is effectively separating the said isomers by distillation and utilizing the distilled allyl products for isomerization separately to form the corresponding propenyl derivatives (5 and 5a) at a temperature of about 50° to 180°C employing alkali metal hydroxides like potassium hydroxide, sodium hydroxide and the like, with a suitable protic solvent selected from methanol, ethanol, propanol, isopropanol, butanol and the like. The amount of metal hydroxide used is about 2 to 10 mole % based on the weight of the allyl compound used and the volume of solvent used in millilitres or litres is with respect to the weight of the allyl compound used. This isomerisation is also effected by using metal catalyst such as palladium composited on carbon, rhodium composited on activated alumina or silica, ruthenium composited on silica or alumina, platinum composited on silica, and the like. The reaction time is in the range of about 5 to 45 hrs, preferably 15 to 24 hrs. If alkali metal hydroxides and alcoholic solvent are employed, after completion of the reaction, the reaction mass is concentrated, cooled to below 40°C; diluted with water, neutralized with dilute (about 10 %) mineral acids such as sulphuric acid, hydrochloric acid and the like to pH 5 to 7, preferably to pH 6-6.5. the reaction mass is filtered and extracted with a suitable solvent such as methylene dichloride, chloroform, dichloroethane, toluene, hexanes, heptanes, diethyl ether, isopropyl ether and the like. The solvent is distilled off to recover the desired compound in good yield. If only metal catalysts are employed, the catalyst is filtered off after the reaction to obtain the desired propenyl compound in good yield. The crude propenyl compounds (5 and 5a) thus obtained are oxidized to benzaldehydes (6 and 6a) using oxidants such as potassium permanganate, sodium periodate, potassium periodate, osmium tetroxide, potassium permanganate/SiO2 or acidic alumina mixture and the like; the preferred oxidizing agent is potassium permanganate. Suitable organic solvents such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, water, and the like in about 3 to 50 volumes based on the weight of the propenyl compound used. Phase transfer catalysts like benzyl triethyl ammonium chloride, tetra butyl ammonium bromide, cetrimide, tetra butyl ammonium hydroxide, tri-n-octyl ammonium bromide and the like are also be employed to speed up the oxidation reaction. The temperature of the reaction ranges from 0° to 50°C and the preferred temperature range is 0° to 10°C. The quantity of oxidizing agents employed is in the range of about 0.2 to 10 mole % based on the actual mole % of the propenyl compounds (5 and 5a) used. After completion of the reaction, the reaction mass is treated at about 0° to 35°C with acidic reagents such as dilute (about 2-6 % aqueous) sulfuric acid, dilute hydrochloric acid and the like. Thereafter, reaction mass is filtered to recover the useful inorganic byproduct (MnO2), if potassium permanganate is used for the reaction. If the solvent is an organic solvent, the organic filtrate is distilled off to obtain the desired aldehyde products (6 and 6a). If the reaction solvent is water, the product may be extracted from the aqueous filtrate with one of the solvents such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, water, and the like. Distillation of solvent gives the expected aldehyde products (6 and 6a) in good yield and purity. These aldehyde products thus obtained are subjected to oxidation with organic peroxides such as perbenzoic acid, meta-chloroperbenzoic acid, performic acid, peracetic acid and the like or with an inorganic peroxide like hydrogen peroxide (30 %) in a suitable medium with or without the use of a catalyst to obtain the corresponding alkoxy phenols (7 and 7a) in good yield. Further, these phenolic compounds thus obtained are alkylated in presence of a suitable base, solvent and an alkylating agent. The ratio of phenolic mixture, alkylating agent, base and the ketonic solvent is 1: 1: 1:4. The alkylating agent is selected from the group consisting of dimethyl sulphate, diethyl sulphate, methyl iodide, ethyl iodide, ethyl bromide, substituted and unsubstituted alkyl, aralkyl, and alkyl halides derived from heterocyclic compounds to obtain corresponding dialkoxybenzenes (8 and 8a). The dialkoxybenzenes are dealkylated in the presence of an acid selected from the group consisting of aqueous hydrobromic acid, hydrochloric acid, borontribromide in dichloromethane or dichloroethane to obtain the targeted products (8, R1=R2=H and 8a, R1=R2=H) in good yield with high purity. /Ul of the above-mentioned reactions are monitored by TLC, GC or HPLC methods. Having generally discussed this invention, a further understanding can be obtained from the following specific examples that are provided herein for the purpose of illustrating the present invention but are not intended to limit the scope in any way. Example 1 Production of l-fluoro-2,3-diethoxybenzene (8, R=F, R1=R2=C2H5) A) Preparation of 2-fluoroallylphenylether (2, R=F) To a mixture of 2-fluorophenol (1, R=F, 500 g, 4.46 moles), acetone (1,500 ml), and potassium carbonate (616 g, 4.46 moles) at 55-60 °C is added allyl bromide (540 g, 4.46 moles), for about 1 hr. After addition, the reaction mixture is stirred for 3-4 hrs. The reaction is monitored by TLC. After completion of reaction, the reaction mass is concentrated, cooled to about 30 °C and quenched with water (2,500 ml). The layers are allowed to separate during about half an hour. The organic layer is separated, washed with water (2 x 500 ml), dried over anhydrous sodium sulphate to obtain 675 g (98 % yield) of 2-fluoroallylphenylether (2, R=F) with a GC purity of 99%. B) Preparation of isomeric 2-allyl-6-fluorophenol (3, R=F) and 4-aIlyl-2-fluoropheno] (3a, R=F) A solution of the 2-fluoroallylphenyl ether (2, R=F, 670 g) in N-methyl pyrrolidinone (1,350 ml) is heated to about 195 °C in an atmosphere of nitrogen for 5-6 hrs. The reaction is monitored by TLC. After completion of the reaction, the reaction mass is cooled to room temperature and water (3,000 ml) is added under stirring. The layers are allowed to separate. The organic layer is separated and washed with water (500 ml x 2). The aqueous layer is extracted with dichloromethane (500 ml) and washed with water (100 ml). The combined organic layers are concentrated to obtain the desired product 670 g (97% yield) in about 85 % ortho and about 15 % para isomeric products. C) Preparation of isomeric 2-aIlyl-6-fluoroethylphenylether (4, R=F, R1=C2H5) and 4- allyl-2-fluoroethylphenyl ether (4a, R=F, R1=C2H5) To a stirred mixture of anhydrous potassium carbonate (613 g, 4.4 moles) in acetone (2.7 L) at 25°-30°C is added the crude mixture of 2-ally 6-fluoro (3, R=F) and 4-allyl-2-fluoro(3a, R=F) phenols (675 g, 4.4 moles) under stirring. The reaction mixture is heated to 55° to 60°C and to this hot slurry is added diethyl sulphate (684 g, 4.4 moles) over a period of 1.5 to 2 hrs. The reaction is monitored by TLC. After completion of reaction, the reaction mass is concentrated under vacuum, cooled to 25-30° C, and quenched with water (1.5 L). The organic layer is separated and washed with water (100 ml) and dried over anhydrous sodium sulphate to obtain the desired crude product in 780 g yield. The crude product was fractionally distilled under vacuum to obtain the desired ortho (4, 620 g GC: 94%, bp 48-50°C at 0.3 mm) and, para (4a, 100 g, 60-65°C at 0.3mm) isomeric products. D) Preparation of crude 6-fluoro-2-propenylethylphenylether (5, R=F, R1=C2H5) To a stirred solution of KOH (620 g, 11.02 moles) in methanol (620 ml) at 65° to 70°C is added 2-allyl-6-fluoroethylphenylether (4, R=F, R1=C2Hs, 620 g, 3.5 moles) over a period of 1 hr. The reaction is maintained at 65° to 70°C for 24 hrs and monitored by TLC. After completion of reaction, the reaction mass is cooled to about 10°C and dilute sulphuric acid (516 g in 3.5 L water) is added over a period of 1 hr. The reaction mixture is filtered through hyflo and the filtrate is extracted with methylenedichloride (lx 2L). The methylenedichloride solution is washed with water (500 ml), and the solvent is removed by distillation to get 576 g (85% yield) pf 6-fluoro-2-propenylethylphenylether (5, R=F, R1=C2H5) with a GC purity of 89%. E) Preparation of crude 2-ethoxy-3-fluorobenzaldehyde (6, R=F, Ri=C2Hs) To a mixture of 6-fluoro-2-propenylethylphenylether (5, R=F, R1=C2H5, 576 g, 2.72 mole), benzyltriethylammonium chloride (865 g, 3.8 moles) in methylenedichloride (4.5 L) at 0°C, freshly grounded potassium permanganate (645 g, 4.08 moles) is added portion wise over a period of 1 hr. The reaction mass is stirred at 0°C for 1 hr and monitored the reaction by TLC. After completion of the reaction, concentrated sulphuric acid (60 g, in 6.2 L water) is added for 1 to 2 hrs. After cooling the mixture to room temperature, the slurry is filtered through hyflo, and washed the bed with methylenedichloride (600 ml). The organic layer is separated, washed with saturated solution of sodium bicarbonate (2x1 L), washed with water (500 ml), and dried over anhydrous magnesium sulphate. Solvent is removed to obtain 460 g (92%yield) of 2-ethoxy-3-fluorobenzaldehyde (6, R=F, R1=C2H5) with a GC purity of 92 %. F) Preparation of crude 2-ethoxy-3-fluorophenol (7, R=F, R1=C2H5) Method A: To a stirred solution of m-chloroperbenzoic acid (70 %, 1095 g, 6.3 moles) in methylenedichloride (7.4 L), is added 2-ethoxy-3-fluorobenzaldehyde (6, R=F, R1=C2H5, 496 g, 2.7 moles) at room temperature. The reaction mass is stirred overnight at room temperature, and the reaction is monitored by TLC. After completion of reaction, the mixture is filtered and the filtrate is concentrated under vacuum to a residue. The intermediate compound thus obtained is dissolved in methanol (1L), KOH (2L, 10 %) is added at about 10°C and the reaction mixture is stirred at room temperature for 1 hr. Thereafter, methanol is distilled off and the resultant aqueous solution is neutralized with con. HC1 (500 ml), the pH is adjusted to 5-6.5, and filtered. The aqueous layer is extracted with methylenedichloride (2.6 L), and washed with aqueous sodium bicarbonate solution (600 ml, 10 %). The solvent is removed by distillation to obtain 2-ethoxy-3-fluorophenol (7, R=F, R1=C2H5) in 248 g (54 % yield) with a GC purity of 98%. Method B: To a stirred solution of formic acid (98 %, 2,472 g, 53.7 moles) and hydrogen peroxide (30 %, 1,328 g, 39 moles) is added 2-ethoxy-3-fluorobenzaldehyde (6, R=F, R1=C2H5, 496 g, 2.68 moles) in methylenedichloride (1.49 L) at room temperature. The reaction mass is heated to 35° to 40°C for 24 hrs and the reaction is monitored by TLC. After the completion of reaction, the reaction mass is cooled to room temperature and allowed the layers to separate. The methylenedichloride layer is separated and concentrated. To the resulting residue methanol (1L) and 10 % KOH (2 L) are added at about 10°C, and the resulting mixture is stirred at room i temperature for 1 hr. The alkali solution is concentrated to remove methanol and neutralized with dilute hydrochloric acid (400 ml) to pH 2-4. The product is extracted from the aqueous layer with methylenedichloride (1.5 L), washed with saturated solution of sodium bicarbonate (500 ml), dried over anhydrous magnesium chloride and distilled to obtain 315 g (68 %yield) of 2-ethoxy-3-fluorophenol (7, R=F, R1=C2H5) with a GC purity of 98 %. G) Preparation of l-fluoro-2,3-diethoxy benzene (8, R=F, R1= R2=C2H5) To a stirred mixture of anhydrous potassium carbonate (269 g, 1.94 moles) in acetone (900 ml) at room temperature, is added 2-ethoxy-3-fluorophenol (7, R=F, R1=C2H5, 315 g, 1.948 moles) under stirring. The reaction mixture is heated to 55° to 60°C and to this hot slurry is added diethyl sulphate (451 g, 2.93 moles) over a period of 1.5 to 2 hrs and the reaction is monitored by TLC. After completion of the reaction, the reaction mass is concentrated and quenched with water (1.5 L). The organic layer is separated, washed with water (500 ml), concentrated and dried over anhydrous sodium sulphate to obtain 360 g (97 % yield) of l-fluoro-2, 3-diethoxy benzene (8, R=F, R1= R2=C2H5) with HPLC purity 99.5 %. Example 2 Preparation of 3-fluorocatechol (8, R=F, R1=R2=H) A mixture of 2-ethoxy-3-fluorophenol (7, R=F, R1=C2H5, 25 g, 0.16 moles), aqueous hydrobromic acid (47 %, 138 ml, 5.0 moles) in acetic acid (175 ml) is slowly heated to about 110-115°C under stirring and maintained it for about 24 hrs. The reaction is monitored by TLC. After completion of the reaction, the reaction mass is concentrated under vacuum. The residue thus obtained is cooled to room temperature and treated with water (75 ml). The product is extracted with methylenedichloride (150 ml). After the usual work-up gave 3-fluorocatechol (8, R=F, R1,=R2=H) in 18.6 g (90 %yield) with HPLC purity 98 %. Advantages of the present invention 1. The process of the present invention is a multi-step process involving a simple efficient and economically viable approach for industrial production by adopting easily available cheaper raw materials. 2. The process of the present invention involves a simple work up and isolation procedure for intermediates and products. 3. The process of the present invention involves use of crude intermediates without further purifications by distillations in the subsequent steps. 4. The process of the present invention gives excellent yields of intermediates and final products with excellent purity A 5. The process of the present invention involves use of non hazardous chemicals resulting in release of non-hazardous effluents.

Full Text

FORM 2
THE PATENTS ACT 1970 (39 of 1970)
&
The Patent Rules 2005
COMPLETE SPECIFICATION
, (see sections 10 & rule 13)
1. TITLE OF THE INVENTION
“A PROCESS FOR THE PREPARATION 3-SUBSTITUTED-l, 2-DIHYDROXYBENZENE, 2-SUBSTITUTED-l, 4-DIHYDROXY BENZENE AND THEIR DERIVATIVES THEREOF”
2. APPLICANT (S)
NAME I NATIONALITY I ADDRESS
HIKAL LIMITED AN INDIAN COMPANY 32/1, Kalena Agrahara,
Banneraghatta Road, BANGALORE 560 076
3. PREAMBLE TO THE DESCRIPTION
COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed.

A PROCESS FOR THE PREPARATION OF 3-SUBSTITUTED-l, 2-DIHYDROXYBENZENE, 2-SUBSTITUTED-l, 4-DIHYDROXY BENZENE AND THEIR DERIVATIVES THEREOF
Field of the invention
The present invention relates to process for the preparation of 3 -substituted- 1,2-dihydroxybenzene (I), 2-substituted-1, 4-dihydroxybenzene (II) and their symmetric and unsymmetrical O-alkyl, aralkyl, substituted and unsubstituted alkyl or aralkyl derivatives from 2-substituted phenols and an allyl halide.
Background of the invention
1, 2-dihydroxybenzenes i.e., catechols exhibit a variety of molecular modes of action in biological Systems and have attracted the attention of the pharmaceutical industry. Among the catechols in general, catechols that have a substituent on 3-position are of particular interest. 3-fluorocatechol and its alkoxy derivatives are potential precursors in the synthesis of a wide range of Pharmaceuticals such as adrenergic catecholamine, biogenic amines and the recent 2-iminopyrrolidine derivatives as thrombin receptor antagonists.
Few methods are available which either give a very poor to moderate yield or unselective methods utilizing 2-substituted phenol particularly 2-fluorophenol as a key starting material. They also involve elaborative approach, much expensive, raw materials, and use of expensive organometallic reagents, which lead to problems with handling, safety, and waste disposal. Some of the methods also involve troublesome laborious biochemical approach giving very poor yield and difficulty in scale-up for large-scale industrial production.
For example, Hansen et al., (Tetrahedron Lett 46, 2005, 3357-3358) have reported a surprising yield of 66 % for 3-fluorocatechol employing a typical procedure reported for 3-bromocatechol, Which involves magnesium chloride, para formaldehyde, triethyl amine base and tetrahydrofuran solvent in an atmosphere of Argon. According to their procedure, insitu oxidation of the expected 3-fluorosalicylaldehyde gives 3-fluorocatechol.
Lynch et al., (J. Biotechnol, 58,1997, 167-175) have disclosed the preparation of 3-fluorocatechol from fluorobenzene by utilizing pseudomonas putida ML2 biocatalyst. This method involves a longer reaction time, huge reaction mass volume and as a whole is laborious and the yield is rather poor for industrial scale-up.
Finkelstein et al., (Applied and Environmental Microbiology, Vol.66, 2000, 2148-2153) have described the preparation of 3-fluorocatechol from 2-fluorophenol by a biochemical

transformation. Again this method is low yielding, troublesome, time consuming and doesn't fit for large scale industrial production.
Other workers like Martan et al. in US 4124643 have disclosed a method for preparing 2-allyl-6-fluorophenol with only 88% conversion of 2-fluorophenol employing allyl chloride as other starting material. In their art, the reaction is not completed and involves purification of the product by vacuum distillation resulting in only 76.6 % molar yield. In the next stage, the process involved Claisen’s type rearrangement of allyl-2-fluorophenylether in the presence of t-butylhydroxyanisole as an antioxidant and sodium carbonate as a base catalyst under nitrogen atmosphere. The disadvantage of this step is that it gives low yield and involves distillation procedures. Ladd et al. (Synth. Commun., 15(1), 1985, 61-69) have reported a process for producing 1-fluoro-2, 3-dimethoxybenzene (8, R=F, R1=R2=CH3) starting from 2-fluorophenol (1, R=F) and allyl bromide. In their method the first step involves extraction of the product with ether solvent after quenching the cooled reaction mass with water. The disadvantage of this method is that it is expensive, involves unnecessary extraction of the product with a solvent and distillation of the product leading to 85 % molar yield only. The overall yield of the targeted product is only about 40%.
Recently, Suzuki et al. in US 20050004204, have disclosed a process for preparing 1, 2-diethoxy-3-fluorobenzene (8, R=F, R1= R2=C2H5) starting from expensive 3-fluorocatechol (8, R=F, R1= R2=H) and ethyl iodide utilizing dimethyl formamide as solvent. The disadvantage of this process is that it is expensive, low yielding and involves purification of product by column chromatography.
The novel and inventive feature of the present invention is that it involves a new sequence for producing potential precursors for a wide range of modern pharmaceutical ingredients with high yield and purity, which has never discussed before for small scale or large scale industrial productions.
Objects of the present invention
It is therefore the primary object of this invention to provide an improved and efficient process for the preparation of 3-substituted-l,2-dihydroxybenzene (I), 2-substituted-l, 4-dihydroxybenzene (II) and their symmetric and unsymmetrical O-alkyl, aralkyl, substituted and unsubstituted alkyl or aralkyl derivatives from 2-substituted phenols and an allyl halide.

An object of the present invention is to provide a process for the production of the substituted
dihydroxy benzene compounds and their derivatives that is cost effective and doesn't generate a
significant amount of unwanted/ unrecoverable waste or byproduct.
Another object of the present invention is to provide a process for the production of the substituted
dihydroxy benzene compounds and their derivatives in high yields and quality without extensive
purifications, special equipments or extra set-up in industries.
Still another object of the present invention is to provide a process for the production of the
substituted dihydroxy benzene compounds and their derivatives for industrial scale up.
Further object of the present invention is to provide a process for the production of substituted
dihydroxy benzene compounds and their derivatives by providing a safe handling method which
does not use expensive organometallics, troublesome approach towards work up, isolation and
purification of intermediates and products.
Yet another object of the present invention to provide a process for the production of substituted
dihydroxy benzene compounds and their derivatives which does not involve waste disposal
problems.
Summary of the present invention
Accordingly, the present invention relates to a process for the preparation of 3-substituted-l, 2-
dihydroxybenzene (I), 2-substituted-l, 4-dihydroxybenzene (II) and their derivatives thereof in a
series of steps.
wherein R represents hydrogen atom or a halogen selected from F or Cl or Br, or NO2, wherein R1 and R2 represent hydrogen or a C1-C4 alkyl, substituted and unsubstituted alkyl, aralkyl, heteroalkyl groups, wherein R1and R2 are identical or different, said process comprising the steps of; reacting 2-substituted phenol with an allyl halide in the presence of a base of reduced particle size and a solvent to obtain a substituted allyl phenyl ether; rearranging the allyl phenyl ether in the presence of a suitable solvent to obtain an isomeric phenol mixture; alkylating the isomeric phenol mixture with a suitable base, a ketonic solvent and an alkylating agent; separating the isomeric compounds by fractional distillation to obtain allyl compounds; isomerising the allyl compounds in the presence of a metallic hydroxide and an alcoholic solvent to obtain crude propenyl benzene

derivatives; diluting the crude propenyl benzene derivatives with water and neutralizing with mineral acid to obtain aqueous filtrate of propenyl benzene derivatives followed by the isolation of propenyl benzene derivatives in the presence of a suitable solvent, oxidizing the aqueous filtrate of neutralized propenyl benzene derivatives to corresponding benzaldehydes in the presence of oxidants, a halo hydrocarbon solvent and a phase transfer catalyst; oxidizing further the benzaldehydes with a suitable peroxide in a halo hydrocarbon solvent to obtain corresponding phenols; alkylating the phenols with a suitable base, solvent and an alkylating agent to obtain corresponding dialkoxybenzenes; and dealkylating the dialkoxybenzenes in the presence of an acid to obtain corresponding dihydroxy benzenes of formula I & II and their symmetric and unsymmetrical O-alkyl, aralkyl, substituted and unsubstituted alkyl or aralkyl derivatives in quantitative yield and with high purity. Detailed description of the of the present invention
Accordingly, the present invention provides a process for producing 3-substituted-1, 2-dihydroxybenzene (I), 2~substituted-l, 4-dihydroxybenzene (II) and their alkyl derivatives and more particularly 3-substituted catechol (8, R1= R2 =H) and its methyl and ethyl derivatives of the following structural formulae, whereby greater yields of the desired products are obtained.
> 11
wherein R represents hydrogen atom or a halogen selected from F or Cl or Br, or NO2, wherein R1 and R2 represent hydrogen or a C1-C4 alkyl, substituted and unsubstituted alkyl, aralkyl, heteroalkyl groups, wherein R1 and R2 are identical or different. The reaction scheme of the present process is as follows:

SCHEME

i : Allyl halide, acetone, K2CO35 ~60 °C, 4-5 hrs.
ii : Heat, N-methyl pyrrolidinone, ~ 195 °C, 5-6 hrs.
iii, vii : Alkylating agent, Acetone, K2CO3, heat, ~ 60 °C, 5-6 hrs.
iv : KOH / methanol, heat, 60-70 °C, 24 hrs.
v : KMnCV Methylenedichloride, Benzyl triethyl ammonium
chloride, 0-5 °C, 1-2 hrs.
vi : m-Chloroperbenzoic acid/Methylenedichloride, or H2O2/
HCO2H, 35-40 °C, 24 hrs.
The first step of the present invention comprises heating 2-substituted phenol(l) with a suitable basic material in presence of an organic solvent under stirring and dropping a suitable allyl halide in to the reaction vessel over a period of 4-5 hr. The reaction is carried out with in a temperature range of about 25° to 110°C, preferably between about 25° to 80°C and most preferably between about 50° to 70°C. Allyl halides used are allyl chloride, allyl bromide, allyl iodide, and the like in an amount of 1-4 mole % and the preferred halide quantity is 1-2,5 mole %. The basic material includes a basic metal carbonate or hydroxide. For example, basic or alkaline reagents which may be used comprise sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, lithium

carbonate, magnesium carbonate, cesium carbonate and the like in an amount of 1-4 mole %. Potassium carbonate is the usually preferred reagent, which is free of water of crystallization and Which has to be brought to a fine particle size by milling, for example in ball mills or pinned-disk mills. Potassium carbonate having fine particle fraction of 85% or smaller than 0.1 mm and 70 % or smaller than 0.05 mm is practically suitable. While the organic solvents used are acetone, methylethylketone, dipropylketone, methylpropylketone, hydrocarbon solvents such as hexanes, heptanes, cyclohexane, and the like in a 2-15 times by volume per mole of phenol compound used. Reaction may be carried out at atmospheric pressure or super atmospheric pressure ranging from about 1 to 50 atmospheres is used for the reaction. Time that is needed for addition of allyl halide into a reaction flask of 2-substituted phenol may be approximately in the range of about Ihr to 4 hrs, preferably addition time is in the range of about 1.5 to 2.5 hrs. After completion of the “eaction, the reaction mass is concentrated, cooled and quenched as such with water. The layers are illowed to separate for about 0.5 to Ihr. The separated organic layer is given water wash and dried )n a suitable drying agent such as anhydrous sodium sulphate, anhydrous magnesium sulphate and he like. The amount of water used for quenching the reaction mass be about 4-15 times based on he weight of the phenol used for the reaction.
Thereafter, the crude ortho substituted allyl phenyl ether (2) which is thus obtained is heated to 180-225 °C quickly in a suitable solvent to effect a Claisen's type rearrangement for a time period of about 2.5 hrs to 12 hrs in an atmosphere of nitrogen, preferably at about 195° to 205°C. The solvents used comprise N-methyl pyrrolidinone, diphenyl ether, decaline, N,N-diethylaniline, and the like and preferably N-methyl pyrrolidinone, since it is easily removed from the product by washing with water. The amount of solvent used is about 0.75 to 4.0 volumes based on the weight of the allyl phenyl ether used for the rearrangement and preferably in the range 1.5 to 2.5 volumes of the solvent. After completion of rearrangement reaction, the reaction mass is cooled and quenched with water. The layers are allowed to separate during a period of about 0.5 to Ihr and the separated organic layer is given brine wash in a volume of 1: 2 ratio based on the weight of starting material used. The aqueous layer is extracted with a suitable halohydrocarbon solvent such as dichloromethane, chloroform, dichloroethane and the like, in an amount of approximately 1-3 volumes of the solvent based on the weight of the starting material used. Washing the organic extract with water and removing the solvent by distillation may offer about 2-5 % of the additional product, which is added to the main organic layer.

The thus formed crude 2-allyl-6-substituted phenol (3) and 4~allyl-2-substituted phenol (3a) mixture is alkylated without further purification with an alkylating agent, utilizing a basic material and a solvent. The alkylating agent is selected from the group of methyl and ethyl esters of sulphuric acid, alkyl halides such as methyl iodide, ethyl iodide, ethyl bromide, propyl bromide propyl iodide, isopropyl bromide, butyl bromide and the like, in an amount of about 1 to 10 mole % based on the total weight of the isomeric phenol mixture and considering 1:1 yield ratio from the previous step reaction. The solvents, basic materials employed including their quantities and particle size, temperature of the reaction are the same as mentioned above for allylation of 2-substituted phenols (1). After completion of the reaction, the reaction mass is cooled to about 15-35°C, preferably about 25-30°C, quenched with water in 3-10 volumes based on the weight of the starting material used and the layers are separated. The organic layer is washed with brine or water (5-10 % by volume based on the weight of the starting compound) to remove the adhered inorganics and trace of the used solvent.
The mixture of crude ortho allyl product (4) and para allyl product (4a) is taken to the subsequent isomerization step or separated almost completely by fractional distillation technique. The ideal and most advantageous method is effectively separating the said isomers by distillation and utilizing the distilled allyl products for isomerization separately to form the corresponding propenyl derivatives (5 and 5a) at a temperature of about 50° to 180°C employing alkali metal hydroxides like potassium hydroxide, sodium hydroxide and the like, with a suitable protic solvent selected from methanol, ethanol, propanol, isopropanol, butanol and the like. The amount of metal hydroxide used is about 2 to 10 mole % based on the weight of the allyl compound used and the volume of solvent used in millilitres or litres is with respect to the weight of the allyl compound used. This isomerisation is also effected by using metal catalyst such as palladium composited on carbon, rhodium composited on activated alumina or silica, ruthenium composited on silica or alumina, platinum composited on silica, and the like. The reaction time is in the range of about 5 to 45 hrs, preferably 15 to 24 hrs.
If alkali metal hydroxides and alcoholic solvent are employed, after completion of the reaction, the reaction mass is concentrated, cooled to below 40°C; diluted with water, neutralized with dilute (about 10 %) mineral acids such as sulphuric acid, hydrochloric acid and the like to pH 5 to 7, preferably to pH 6-6.5. the reaction mass is filtered and extracted with a suitable solvent such as methylene dichloride, chloroform, dichloroethane, toluene, hexanes, heptanes, diethyl ether, isopropyl ether and the like. The solvent is distilled off to recover the desired compound in good

yield. If only metal catalysts are employed, the catalyst is filtered off after the reaction to obtain the desired propenyl compound in good yield.
The crude propenyl compounds (5 and 5a) thus obtained are oxidized to benzaldehydes (6 and 6a) using oxidants such as potassium permanganate, sodium periodate, potassium periodate, osmium tetroxide, potassium permanganate/SiO2 or acidic alumina mixture and the like; the preferred oxidizing agent is potassium permanganate. Suitable organic solvents such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, water, and the like in about 3 to 50 volumes based on the weight of the propenyl compound used. Phase transfer catalysts like benzyl triethyl ammonium chloride, tetra butyl ammonium bromide, cetrimide, tetra butyl ammonium hydroxide, tri-n-octyl ammonium bromide and the like are also be employed to speed up the oxidation reaction. The temperature of the reaction ranges from 0° to 50°C and the preferred temperature range is 0° to 10°C. The quantity of oxidizing agents employed is in the range of about 0.2 to 10 mole % based on the actual mole % of the propenyl compounds (5 and 5a) used. After completion of the reaction, the reaction mass is treated at about 0° to 35°C with acidic reagents such as dilute (about 2-6 % aqueous) sulfuric acid, dilute hydrochloric acid and the like. Thereafter, reaction mass is filtered to recover the useful inorganic byproduct (MnO2), if potassium permanganate is used for the reaction. If the solvent is an organic solvent, the organic filtrate is distilled off to obtain the desired aldehyde products (6 and 6a). If the reaction solvent is water, the product may be extracted from the aqueous filtrate with one of the solvents such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, water, and the like. Distillation of solvent gives the expected aldehyde products (6 and 6a) in good yield and purity. These aldehyde products thus obtained are subjected to oxidation with organic peroxides such as perbenzoic acid, meta-chloroperbenzoic acid, performic acid, peracetic acid and the like or with an inorganic peroxide like hydrogen peroxide (30 %) in a suitable medium with or without the use of a catalyst to obtain the corresponding alkoxy phenols (7 and 7a) in good yield. Further, these phenolic compounds thus obtained are alkylated in presence of a suitable base, solvent and an alkylating agent. The ratio of phenolic mixture, alkylating agent, base and the ketonic solvent is 1: 1: 1:4. The alkylating agent is selected from the group consisting of dimethyl sulphate, diethyl sulphate, methyl iodide, ethyl iodide, ethyl bromide, substituted and unsubstituted alkyl, aralkyl, and alkyl halides derived from heterocyclic compounds to obtain corresponding dialkoxybenzenes (8 and 8a).

The dialkoxybenzenes are dealkylated in the presence of an acid selected from the group
consisting of aqueous hydrobromic acid, hydrochloric acid, borontribromide in
dichloromethane or dichloroethane to obtain the targeted products (8, R1=R2=H and 8a,
R1=R2=H) in good yield with high purity.
/Ul of the above-mentioned reactions are monitored by TLC, GC or HPLC methods.
Having generally discussed this invention, a further understanding can be obtained from the
following specific examples that are provided herein for the purpose of illustrating the present
invention but are not intended to limit the scope in any way.
Example 1 Production of l-fluoro-2,3-diethoxybenzene (8, R=F, R1=R2=C2H5)
A) Preparation of 2-fluoroallylphenylether (2, R=F)
To a mixture of 2-fluorophenol (1, R=F, 500 g, 4.46 moles), acetone (1,500 ml), and potassium carbonate (616 g, 4.46 moles) at 55-60 °C is added allyl bromide (540 g, 4.46 moles), for about 1 hr. After addition, the reaction mixture is stirred for 3-4 hrs. The reaction is monitored by TLC. After completion of reaction, the reaction mass is concentrated, cooled to about 30 °C and quenched with water (2,500 ml). The layers are allowed to separate during about half an hour. The organic layer is separated, washed with water (2 x 500 ml), dried over anhydrous sodium sulphate to obtain 675 g (98 % yield) of 2-fluoroallylphenylether (2, R=F) with a GC purity of 99%.
B) Preparation of isomeric 2-allyl-6-fluorophenol (3, R=F) and 4-aIlyl-2-fluoropheno] (3a,
R=F)
A solution of the 2-fluoroallylphenyl ether (2, R=F, 670 g) in N-methyl pyrrolidinone (1,350 ml) is heated to about 195 °C in an atmosphere of nitrogen for 5-6 hrs. The reaction is monitored by TLC. After completion of the reaction, the reaction mass is cooled to room temperature and water (3,000 ml) is added under stirring. The layers are allowed to separate. The organic layer is separated and washed with water (500 ml x 2). The aqueous layer is extracted with dichloromethane (500 ml) and washed with water (100 ml). The combined organic layers are concentrated to obtain the desired product 670 g (97% yield) in about 85 % ortho and about 15 % para isomeric products.
C) Preparation of isomeric 2-aIlyl-6-fluoroethylphenylether (4, R=F, R1=C2H5) and 4-
allyl-2-fluoroethylphenyl ether (4a, R=F, R1=C2H5)

To a stirred mixture of anhydrous potassium carbonate (613 g, 4.4 moles) in acetone (2.7 L) at 25°-30°C is added the crude mixture of 2-ally 6-fluoro (3, R=F) and 4-allyl-2-fluoro(3a, R=F) phenols (675 g, 4.4 moles) under stirring. The reaction mixture is heated to 55° to 60°C and to this hot slurry is added diethyl sulphate (684 g, 4.4 moles) over a period of 1.5 to 2 hrs. The reaction is monitored by TLC. After completion of reaction, the reaction mass is concentrated under vacuum, cooled to 25-30° C, and quenched with water (1.5 L). The organic layer is separated and washed with water (100 ml) and dried over anhydrous sodium sulphate to obtain the desired crude product in 780 g yield. The crude product was fractionally distilled under vacuum to obtain the desired ortho (4, 620 g GC: 94%, bp 48-50°C at 0.3 mm) and, para (4a, 100 g, 60-65°C at 0.3mm) isomeric products.
D) Preparation of crude 6-fluoro-2-propenylethylphenylether (5, R=F, R1=C2H5)
To a stirred solution of KOH (620 g, 11.02 moles) in methanol (620 ml) at 65° to 70°C is added 2-allyl-6-fluoroethylphenylether (4, R=F, R1=C2Hs, 620 g, 3.5 moles) over a period of 1 hr. The reaction is maintained at 65° to 70°C for 24 hrs and monitored by TLC. After completion of reaction, the reaction mass is cooled to about 10°C and dilute sulphuric acid (516 g in 3.5 L water) is added over a period of 1 hr. The reaction mixture is filtered through hyflo and the filtrate is extracted with methylenedichloride (lx 2L). The methylenedichloride solution is washed with water (500 ml), and the solvent is removed by distillation to get 576 g (85% yield) pf 6-fluoro-2-propenylethylphenylether (5, R=F, R1=C2H5) with a GC purity of 89%.
E) Preparation of crude 2-ethoxy-3-fluorobenzaldehyde (6, R=F, Ri=C2Hs)
To a mixture of 6-fluoro-2-propenylethylphenylether (5, R=F, R1=C2H5, 576 g, 2.72 mole), benzyltriethylammonium chloride (865 g, 3.8 moles) in methylenedichloride (4.5 L) at 0°C, freshly grounded potassium permanganate (645 g, 4.08 moles) is added portion wise over a period of 1 hr. The reaction mass is stirred at 0°C for 1 hr and monitored the reaction by TLC. After completion of the reaction, concentrated sulphuric acid (60 g, in 6.2 L water) is added for 1 to 2 hrs. After cooling the mixture to room temperature, the slurry is filtered through hyflo, and washed the bed with methylenedichloride (600 ml). The organic layer is separated, washed with saturated solution of sodium bicarbonate (2x1 L), washed with water (500 ml), and dried over anhydrous magnesium sulphate. Solvent is removed to obtain 460 g (92%yield) of 2-ethoxy-3-fluorobenzaldehyde (6, R=F, R1=C2H5) with a GC purity of 92 %.
F) Preparation of crude 2-ethoxy-3-fluorophenol (7, R=F, R1=C2H5)
Method A:

To a stirred solution of m-chloroperbenzoic acid (70 %, 1095 g, 6.3 moles) in methylenedichloride (7.4 L), is added 2-ethoxy-3-fluorobenzaldehyde (6, R=F, R1=C2H5, 496 g, 2.7 moles) at room temperature. The reaction mass is stirred overnight at room temperature, and the reaction is monitored by TLC. After completion of reaction, the mixture is filtered and the filtrate is concentrated under vacuum to a residue. The intermediate compound thus obtained is dissolved in methanol (1L), KOH (2L, 10 %) is added at about 10°C and the reaction mixture is stirred at room temperature for 1 hr. Thereafter, methanol is distilled off and the resultant aqueous solution is neutralized with con. HC1 (500 ml), the pH is adjusted to 5-6.5, and filtered. The aqueous layer is extracted with methylenedichloride (2.6 L), and washed with aqueous sodium bicarbonate solution (600 ml, 10 %). The solvent is removed by distillation to obtain 2-ethoxy-3-fluorophenol (7, R=F, R1=C2H5) in 248 g (54 % yield) with a GC purity of 98%. Method B:
To a stirred solution of formic acid (98 %, 2,472 g, 53.7 moles) and hydrogen peroxide (30 %, 1,328 g, 39 moles) is added 2-ethoxy-3-fluorobenzaldehyde (6, R=F, R1=C2H5, 496 g, 2.68 moles) in methylenedichloride (1.49 L) at room temperature. The reaction mass is heated to 35° to 40°C for 24 hrs and the reaction is monitored by TLC. After the completion of reaction, the reaction mass is cooled to room temperature and allowed the layers to separate. The methylenedichloride layer is separated and concentrated. To the resulting residue methanol (1L) and 10 % KOH (2 L) are added at about 10°C, and the resulting mixture is stirred at room
i
temperature for 1 hr. The alkali solution is concentrated to remove methanol and neutralized with dilute hydrochloric acid (400 ml) to pH 2-4. The product is extracted from the aqueous layer with methylenedichloride (1.5 L), washed with saturated solution of sodium bicarbonate (500 ml), dried over anhydrous magnesium chloride and distilled to obtain 315 g (68 %yield) of 2-ethoxy-3-fluorophenol (7, R=F, R1=C2H5) with a GC purity of 98 %. G) Preparation of l-fluoro-2,3-diethoxy benzene (8, R=F, R1= R2=C2H5) To a stirred mixture of anhydrous potassium carbonate (269 g, 1.94 moles) in acetone (900 ml) at room temperature, is added 2-ethoxy-3-fluorophenol (7, R=F, R1=C2H5, 315 g, 1.948 moles) under stirring. The reaction mixture is heated to 55° to 60°C and to this hot slurry is added diethyl sulphate (451 g, 2.93 moles) over a period of 1.5 to 2 hrs and the reaction is monitored by TLC. After completion of the reaction, the reaction mass is concentrated and quenched with water (1.5 L). The organic layer is separated, washed with water (500 ml), concentrated and

dried over anhydrous sodium sulphate to obtain 360 g (97 % yield) of l-fluoro-2, 3-diethoxy benzene (8, R=F, R1= R2=C2H5) with HPLC purity 99.5 %.
Example 2 Preparation of 3-fluorocatechol (8, R=F, R1=R2=H)
A mixture of 2-ethoxy-3-fluorophenol (7, R=F, R1=C2H5, 25 g, 0.16 moles), aqueous hydrobromic acid (47 %, 138 ml, 5.0 moles) in acetic acid (175 ml) is slowly heated to about 110-115°C under stirring and maintained it for about 24 hrs. The reaction is monitored by TLC. After completion of the reaction, the reaction mass is concentrated under vacuum. The residue thus obtained is cooled to room temperature and treated with water (75 ml). The product is extracted with methylenedichloride (150 ml). After the usual work-up gave 3-fluorocatechol (8, R=F, R1,=R2=H) in 18.6 g (90 %yield) with HPLC purity 98 %. Advantages of the present invention
1. The process of the present invention is a multi-step process involving a simple efficient and
economically viable approach for industrial production by adopting easily available
cheaper raw materials.
2. The process of the present invention involves a simple work up and isolation procedure for
intermediates and products.
3. The process of the present invention involves use of crude intermediates without further
purifications by distillations in the subsequent steps.
4. The process of the present invention gives excellent yields of intermediates and final
products with excellent purity A
5. The process of the present invention involves use of non hazardous chemicals resulting in
release of non-hazardous effluents.

Documents:

825-che -2006 abstract.pdf

825-che -2006 claims.pdf

825-che -2006 complete description.pdf

825-che -2006 correpondance- others.pdf

825-che -2006 form 1.pdf

825-che -2006 form 26.pdf

825-che -2006 form 3.pdf

825-che -2006 form 5.pdf

825-CHE-2006 EXAMINATION REPORT REPLY RECEIVED 29-05-2012.pdf

825-CHE-2006 AMENDED CLAIMS 18-07-2012.pdf

825-CHE-2006 AMENDED PAGES OF SPECIFICATION 18-07-2012.pdf

825-CHE-2006 CORRESPONDENCE OTHERS 18-07-2012.pdf

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Patent Number

253788

Indian Patent Application Number

825/CHE/2006

PG Journal Number

35/2012

Publication Date

31-Aug-2012

Grant Date

24-Aug-2012

Date of Filing

09-May-2006

Name of Patentee

M/S. HIKAL LIMITED

Applicant Address

32/1 KALENA AGRAHARA, BANNERAGHATTA ROAD, BANGALORE 560 076

Inventors:

#	Inventor's Name	Inventor's Address
1	PRABHSWAMY BASAPPA	HIKAL LTD., 32/1 KALENA AGRAHARA, BANNERAGHATTA ROAD, BANGALORE 560 076
2	GANAGADHARA CHARY RAPAKA	HIKAL LTD., 32/1 KALENA AGRAHARA, BANNERAGHATTA ROAD, BANGALORE 560 076
3	DEVARAJA THIMMASANDRA SEETHA REDDY	HIKAL LTD., 32/1 KALENA AGRAHARA, BANNERAGHATTA ROAD, BANGALORE 560 076
4	RAMAMOHAN MEKALA	HIKAL LTD., 32/1 KALENA AGRAHARA, BANNERAGHATTA ROAD, BANGALORE 560 076
5	RAJENDRA PRASAD GUPTA	HIKAL LTD., 32/1 KALENA AGRAHARA, BANNERAGHATTA ROAD, BANGALORE 560 076
6	MANJUNATHA SOLURU GOPALAN	HIKAL LTD., 32/1 KALENA AGRAHARA, BANNERAGHATTA ROAD, BANGALORE 560 076

PCT International Classification Number

A61K31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA