BACKGROUND OF THE INVENTION Separation of isomeric and non-isomeric close boiling mixtures is often an industrial problem. Of particular interest, herein, are methods of resolving isomeric mixtures, such as mixtures of substituted phenols e. g., hydroxyacetophenones ; and substituted anilines and substituted benzoic acids. The separation of isomeric mixtures is important in chemical process industries. The separation of such substances by physical methods like distillation, crystallization, solvent extraction, etc. is either difficult or economically not viable. There are several chemical processes known for separating closely related organic compounds such as dissociation extraction which exploits the difference in their dissociation constants, reactive distillation, reactive crystallization where a complexing agent is used for the separation, chemical complexation or reactive precipitation with sulfonic acids, etc [Gaikar, V. G. and Sharma, M. M., Sep. Purif Methods, 18 (2) 111 (1989)]. All these methods exploit the difference in the reactivities/acidities of the acidic/phenolic compounds for effective separation. However, the separation is not complete by these methods and multistage contact is necessary.

Acylation of phenol followed by Fries rearrangement gives a mixture of o-and p-hydroxyacetophenones (HAP's). The composition of the product varies from 10% to 95% of o-HAP depending upon the conditions of the reaction and the catalyst. p- Hydroxyacetophenone (p-HAP) is a solid white crystalline powder with a boiling point of 148°C/3mm of Hg. o-Hydroxyacetophenone (o-HAP) is a greenish-yellow liquid at room temperature with a boiling point of 213°C/717mm of Hg. These materials are used as drug intermediates and thus have significant industrial importance. p-HAP is used for the manufacture of Bufexamac (4-Butoxy-N-hydroxyben. eneacetamide) which is used as an anti-inflammatory, analgesic and antipyretic agent. It is also used in

the manufacture of Pixifenide fl-/t l (Hydrotyimino) et/? ylyphenotyX acetyl7piperidine) which is used as an anti-inflammatory agent. o-HAP is used for the manufacture of 4-hydroxycoumarin which is the basic raw material for the manufacture of Acenocoumarol [3- (a-acetonyl-p-nitrobenzyl)-4-hydroxycoumarin] used as an anticoagulant and vitamin K antagonist, Tioclomarol (3- 3- (4-chlorophenyl)-I- (- chloro-2-thienyl)-3-llydroapropyl)-4-hydroEy-2H-I-benzopyran -2-one) used as an anticoagulant and Warfarin Sodium (3-(a-acetonylbenzyl)-4-hydroxycoumarin sodium salt) also used as an anticoagulant.

The separation of the two isomers is carried out by fractional distillation under reduced pressure through an efficient fractionating column or by steam distillation as the o-isomer (being chelated) is more steam volatile. But the separation of these materials by this method is not complete and is also economically not attractive. For the separation by steam distillation, the amount of steam required is very large which also gets contaminated by the dissolved phenolics. There remains thus a need for a method for the resolution of isomers of monosubstituted phenols by chemical means.

OBJECT OF THE INVENTION It is thus basic objective of the present invention to provide a process for producing substantially pure 1,2- substituted benzene compound of Formula 1 and 1,4- substituted benzene compound of Formula 2 separately wherein R, is selected from the group of-OH,-COOH,-NH2, N (R3) (R4) where R3 and R4 are from the group-H, (CH2) nCH3; n=0-4 ; and R2 is selected from the group consisting of- (CO-CH3),- (NH2), (OH),- (N02),- (X),- (OCH3),-COOH,-CHO,- (OCH2CH3) and X is halogen selected from F, CL, Br and I Formula 1 Formula 2

from an isomeric mix of said compounds of Formula 1 and 2 in any proportion.

Another object of the present invention is to provide process for producing said pure compounds of Formula 1 and Formula 2 separately in high yield from said mix of said compounds of Formula 1 and 2.

Yet further object is directed to provide a process for producing said pure compounds of Formula 1 and Formula 2 separately from mix of said compounds of Formula 1 and 2 which would be simple and cost effective to carry out.

SUMMARY OF THE INVENTION Thus according to the present invention there is provided a process for producing isomeric 1, 2 substituted benzene compound of Formula 1 and 1,4 substituted benzene compound of Formula 2 separately wherein R is selected from the group of-OH,-COOH,-NH2, N (R3) (R4) where R3 and R4 are from the group -H, (CH2) nCH3; n = 0-4 ; and R2 is selected from the group consisting of- (CO- CH3),- (NH2),- (OH),- (NO2),- (X),- (OCH3),-COOH,-CHO,- (OCH2CH3) and X is halogen selected from F, CL, Br and I Formula 1 Formula 2 from a binary mixture in any proportions of said isomeric compounds of Formula 1 and 2, comprising the following steps: i) treating the said binary mix with an organic solvent such as herein described to phase separate by preferential solubilisation one of the said two compounds in a solution phase and the other as the substantially pure undissolved compound ;

ii) contacting the solution phase obtained in step (i) above with an ion exchange resin such herein described for preferentially adsorbing and recovering further any of said undissolved compound present in the said solution phase of (i) above to thereby further phase separate from the said compound in said solution phase the other compound as substantially pure undissolved compound; iii) recovering from the said solution phase of step (ii) above the said soluble compound in substantially pure form by desolventising the solution phase in conventional manner.

According to a preferred aspect in the above disclosed process of the present invention the said step of treating said binary mixture with said organic solvent in step (i) comprise further washing said undissolved compound separated with fresh solvent to thereby obtain an additional solution phase containing the soluble compound and a further amount of the substantially pure undissolved compound which is seperated ; and said step of contacting said solution phase with said ion exchange resin, comprise contacting the said solution phase and the said additional solution phase together with said ion exchange resin.

Also preferably in the above process of the invention the adsorbed components of Formula 1 and 2 from said ion exchange resin subsequent to said ion exchange treatment are recovered following: a) treating the said adsorbent ion exchange resin of step (ii) with anyone of an organic polar solvent, aqueous alkali and acid solvent to thereby desorb said compounds of formula 1 and 2 from said resin ; b) recovering the said compound of formula 1 and 2 by desolventising the solution obtained in step (a) above in conventional way and adding back the thus recovered mix of said compounds of Formula 1 and 2 as said binary mix in said step (i) above.

Also to favour economizing the process of the invention the ion exchange resin is regenerated and the solvents recycled in the above process.

The term'isomeric nuxtures'as used herein include mixtures of disubstituted benzenes with the substituent group occupying different positions on the benzene group. The major substituent is generally hydroxyl group (-OH) forming substituted phenols and amino group (NH2) forming substituted anilines. The second substituent group is nitro, chloro, methoxy, ethoxy, hydroxy etc.

The term'preferential solubilization'implies significantly higher solubility of one of the components (o-isomer) in the organic solvent as compared to the other component (p-isomer). The p-isomer will also be soluble in the organic solvent due to the presence of the o-isomer. But such solubilization will not adversely affect the separation process as long as the ratio of the solubilized amount of the o-isomer to that of the p-isomer is extremely high. The selection of the solvent for the first step has to be done based on the solubility data and other properties such as the boiling point, toxicity, etc. The solvent selected should be such in which the solubility of one component is extremely high while that of the other component is comparatively low.

Also, the solvent should not dissolve the ion-exchange resin selected for the adsorption in step (iii).

Organic solvent employed in step (i) is selected from a group of aliphatic, alicyclic, aromatic hydrocarbons, their chlorinated derivatives; ethers; esters; amides and ketones and combinations thereof. For example n-heptane, cyclohexane, toluene are useful for selective/preferential solubilisation of these compounds. n-Aliphatic hydrocarbons are preferred solvents.

Ion exchange resin used in step (iii) is selected from group consisting of polymeric structures with styrene-divinylbenzene as polymeric backbone with primary, secondary or tertiary amine or quaternary ammonium group for acidic mixtures, and sulphonic acid or carboxylic acid as functional group for mixtures of amines; Some of the commercially available ion exchange resins useful in this process are Indion 850, Indion 810, Indion 925, Tulsion A-2X MP, Dowex MSA-1, (These are trade names under which ion exchange resins are available).

The term'preferential adsorption'implies significantly higher adsorption of one of the components on the ion-exchange resin as compared to that of the other component in the mixture. It is recognized that the second component from the extract phase can also adsorb on the same ion-exchange resin, in lesser quantities than the predominantly adsorbed component. Such adsorption is not deleterious to resolution if the ratio of the adsorbed amount of the preferentially adsorbed component to adsorbed amount of other component is high.

The nature and amount of these amino and acidic groups and the presence of aromatic rings in the polymeric structure of the resins are believed to be significant for the adsorption on these ion-exchange resins. The process of invention is particularly suited for the separation of isomeric mixtures of organic acids and bases. Examples of such mixtures include o-/p-hydroxyacetophenones, o-/p-nitroanilines, o-/p- chloroanilines, o-/p-nitrophenols, o-/p-chlorophenols, o-/p-hydroxybenzoic acids, o-/p- hydroxybenzaldehydes, o-/p-aminoacetophenones, etc. Generally, in a mixture of o- and p-substituted compounds, the o-isomer is selectively solubilized in an organic solvent. Also, when the mixture is brought in contact with an ion-exchange resin, the p- isomer is preferentially adsorbed. These two specific selectivities are combined in this process for the complete separation of these mixtures. The following Table shows the compounds which can be separated with corresponding solvents and ion-exchange resins. Rl R2 Solvent (i) Resin functional group Solvent (v) -OH-COCH3 n-Heptane tertiary amine methanol -N02-NH2 n-Heptane sulphonic acid methanol -Cl-NH2n-Heptane sulphonic acid methanol -NH2-COCH3 n-Heptane sulphonic acid methanol -OH-COOH n-Heptane tertiary amine methanol -OH-CHO n-Heptane tertiary amine methanol -COOH-Cl n-Heptane tertiary amine methanol -COOH N02 n-Heptane tertiary amine methanol -COOH-NH2 n-Heptane tertiary amine methanol -OH-N02 n-Heptane tertiary amine methanol

Organic polar solvent employed in step (v) is selected from group consisting of aliphatic alcohols, alicyclic alcohols, aromatic alcohols, esters, ethers, ketones, amides and aqueous alcohols, acids, alkalies and combinations thereof. For example, methanol, ethanol, diethylether, diisopropyl ether, acetone, methyl ethyl ketone, are useful for desorbing these compounds. Methanol, ethanol, acetone are the preferred solvents.

A mixture of the isomers is brought in contact with the selected organic solvent and agitated for a period sufficient for the solubilization to take place. The amount of the solvent utilized is calculated from the solubility of the more soluble isomer. A sufficient time for solubilization is usually 30 minutes. The agitation is conducted at selected temperature and atmospheric pressure. After agitation, the precipitated component is separated from the organic solution by filtration or by decantation. The organic phase containing almost all o-isomer and small quantities of the dissolved p- isomer in the organic solvent is brought into contact with the ion exchange resin (IER) in the form of a slurry or it can be passed through a column packed with the ion exchange resin.

The slurry is agitated for a period sufficient for the adsorption to take place. A typical adsorption time is in the range of 15 min to 2 hrs. The mixing is conducted at selected temperature and atmospheric pressure. After the mixing, the ion-exchange resin is separated from the liquid by decantation or filtration or centrifugation. The separated ion-exchange resin is treated either with polar solvent, such as methanol or with aqueous alkali solution to release the adsorbed organic compounds. This release can be conducted at selected temperature. The ion exchange resin is recovered, dried and recycled for subsequent separation.

The organic compounds liberated from the ion-exchange resin by polar solvent is recovered by fractional distillation. If an aqueous alkali solution is used for liberation of adsorbed phenolic compounds, then the solution is first treated with aqueous mineral acid to neutralize the base and the organic compound is separated as a second phase.

This organic compound can be separated by decantation or filtration or centrifugation.

In another method, the ion exchange resins are packed in a column, with a provision of influent and effluent streams of mixtures, and the organic phase containing almost all o-isomer and small quantities of the dissolved p-isomer in the organic solvent is pumped through the ion exchange resin bed at a specified flow rate wherein preferential adsorption of p-HAP takes place. The effluent from the column is thus pure o-HAP. The effluent from the column is collected till the concentration of p-HAP starts increasing in the effluent. After this concentration, the flow of the mixture solution is stopped and the column is drained of any residual liquid. A flow of alcohol is started through the column in the same direction as the mixture solution or in the opposite direction. The solution at the effluent is collected until the effluent concentration of the hydroxyacetophenones drops to zero. The column is then drained of the solution, dried and used for next cycle of adsorption.

In another method, after stopping the flow of the mixture solution, the column was drained of residual fluid and aqueous alkaline solution is passed through the column until concentration of HAP's in effluent drops to zero. The column is then drained of solution, washed with methanol, dried and used for next cycle of adsorption.

The major advantage of this method is that the mixture of o-and p-isomers can be separated into pure o-and isomers in single equilibrium stage operations by adopting this two step strategy. The process of invention is particularly suited for the separation of isomeric mixtures of organic acids and bases.

Isomeric mixtures susceptible to treatment with the process of invention include o-and p-substituted compounds. Such mixtures include o-/p-hydroxyacetophenones, o- /p-nitroanilines, o-/p-chloroanilines, o-/p-nitrophenols, o-/p-chlorophenols, o-/p- hydroxybenzoic acids, o-/p-hydroxybenzaldehydes, o-/p-aminoacetophenones, etc.

This process gives extraordinarily high recovery and the mutual separation of the isomeric mixtures which would be impossible to attain in single stage distillation.

Also, the solvent can be recovered easily and it can be recycled without significant losses of the component. Another advantage lies in significantly lower energy than physical separation involving vacuum distillation/steam distillation for separation of such mixtures.

EXAMPLES The objects of the invention, its advantages and means for attaining the same are disclosed hereunder in greater detail with reference to non-limiting exemplary embodiments of the same. The examples are by way of illustration only and in no way restrict the scope of the invention.

Chemicals used p-Hydroxyacetophenone (p-HAP) (extrapure grade with 98% purity). o-Hydroxyacetophenone (o-HAP) (synthesis grade with 95% purity) n-Heptane (LR grade) Dichloromethane (LR grade) Ion exchange resin: Indion 850 (Ion Exchange India, Ltd.) Methanol (AR grade) Method of analysis: High Performance Liquid Chromatography with C18 reverse phase column.

Example 1 : A reaction vessel (200moi) equipped with a stirrer was charged with a mixture containing 2.68 gms of o-HAP and 0.22 gms of p-HAP. To this mixture, 50ml of n- heptane was added. This mixture was stirred for a period of 30 minutes at room temperature of 303K. The mixture was filtered to separate the precipitated p-HAP from the organic phase and then washed with pure heptane to give 0.176 gms (80% recovery) in pure form (100% purity). The extract solution phase containing 0.044gms of p-HAP and 2.6 gms of o-HAP as determined by HPLC was taken and 5 grams of macroporous weakly basic ion exchange resin, Indion 850 was added to this solution and kept for shaking for a period of 8 hours. The solution was separated from the resin by decantation. The solution contained 2.55gms by weight of o-HAP (95.15% recovery). This was recovered by solvent removal with a purity of 100%. The resin was then washed with methanol to regenerate the resin for reuse.

Example 2: The example was the same as example 1 except that the quantities of HAP's used were different. The mixture contained 3.6gms of o-HAP and 0.34gms of p-HAP The extract phase contained 0.067gms of p-HAP and 3.5gms of o-HAP After adsorption, the residual solution contained 3.48gms by weight of o-HAP (96.67% recovery) without any trace of p-HAP Example 3: A reaction vessel equipped with a stirring means was charged with 23 ml of solution containing 0.61 gms of o-HAP and 0.62 gms of pHAP in dichloromethane. To this solution, 2.0 gms of dried ion exchange resin, Indion 850 was added to form a slurry. The adsorption was conducted by stirring this mixture for 8 hours at 303K. The mixture was filtered under suction so as to separate the ion exchange resin from the liquid solution. The separated ion exchange resin was washed with dichloromethane.

The filtrate contain 0.21 gms of p-HAP and 0.58 gms of o-HAP (as determined by high performance liquid chromatography).

Example 4: A reaction vessel (200ml) equipped with a stirrer was charged with a mixture containing 35 gms of o-HAP and 1.75 gms of pHAP. To this mixture, 500ml of n- heptane was added. This mixture was stirred for a period of 30 minutes at room temperature of 303K. The mixture was filtered to separate the precipitated p-HAP from the organic phase and then washed with pure heptane (55ml) to give 1.567 gms (89.5% recovery) in pure form (100% purity). The extract solution phase contained 0.183 gms of p-HAP and 35 gms of o-HAP as determined by HPLC.

The extract solution phase was then pumped through a column (2.0 cm diameter and 37 cm height) filled with the ion exchange resin, Indion 850. For the complete passage of the extract solution phase (555ml), no p-HAP was detected in the effluent solution. The recovery of o-HAP in the extract solution was 78.5% (100% purity).

The desorption run was carried out using methanol. When 220ml of methanol was passed through the column, 7.5 gms of o-HAP and 1.83 gms of p-HAP was desorbed.

Chemical used o-Nitrophenol (o-NP) (100% pure) p-Nitrophenol (p-NP) (100% pure) n-Heptane (LR grade) Ion exchange resin: Indion 850, weak base resin (Ion Exchange India, Ltd.) : Indion 810 strong base resin (Ion Exchange India, Ltd.) Example 5: A reaction vessel (200 ml) equipped with a stirrer was charged with a mixture containing 0.48 gms of o-NP and 0.4 gms of p-NP. To this mixture, 50 ml of n-heptane was added. This mixture was stirred for a period of 30 minutes at room temperature of 303 K. The mixture was filtered to separate the precipitated p-NP from the organic phase and then washed with pure heptane to give 0. 3995 gms (99.88% recovery) in pure form (100% purity). The extract solution phase containing 0.0005 gms of p-NP and 0.47 gms of o-NP as determined by tIV-spectrophotometer was taken and 1 grams

of macroporous weakly basic ion exchange resin, Indion 850 was added to this solution and kept for shaking for a period of 8 hours. The solution was separated from the resin by decantation. The solvent was removed by evaporation from the solution to recover 0.45 gms of o-NP (95.74% recovery).

Example 6: The example was the same as Example 5 except that the quantities of NP's and the resin used were different. The mixture contained 5 gms of o-NP and 5 gms of p-NP.

The extract phase contained 0.006 gms of p-NP and 4.7 gms of o-NP. After adsorption of p-NP on Indion 810 resin, the residual solution contained 4.55 gms by weight of o- NP (96.8% recovery) without any trace of pNP.

Chemical used p-Phenylene diamine (p-PDA) (100% pure) o-Phenylene diamine (o-PDA) (100% pure) 1,2-Dichloroethane (LR grade) Ion exchange resin: Indion 840 strong acid resin (Ion Exchange India, Ltd.) Example 7: A reaction vessel equipped with a stirring means was charged with 10 ml of solution containing 0.12 gms (0.93% w/w) of p-PDA and 0.1 gms (0.8% w/w) of o- PDA and 9.8 ml of 1, 2-dichloroethane as a solvent for the phenylenediamines. To this reaction vessel, 0.1 gms of dried ion exchange resin (Indion 840) was added to form a slurry like mixture. The adsorption was run by stirring this mixture for 8 hours at room temperature. The mixture as filtered under suction so as to separate the ion exchange resin from the liquid solution. The filtrate contain 0.042% (w/w) of p-PDA and 0.69% (w/w) of o-PDA as determined by GC using SE-30 column (Perkin Elmer model).

Example 8 : The example was the same as example 7 except thatthe quantities of PDA's used were different. The mixture contained 0.23 gms (1.8% w/w) of o-PDA and 0.21 gms (1.66% w/w) of p-PDA. After adsorption, the filtrate contain 0.718% (w/w) of p- PDA and 1.64% (w/w) of o-PDA as determined by GC.