Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF p-METHOXY PHENYLACETIC ACID FROM p-METHOXY ACETOPHENONE
Abstract	This invention relates to an improved process for the preparation of p-methoxy phenylacetic acid from p-methoxy acetophenone using sulphur, ammonia as reagents and isopropylalcohol as

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This invention relates to an improved process for the preparation of p-methoxy phenylacetic acid from p-methoxy acetophenone using sulphur, ammonia as reagents and isopropylalcohol as media This invention particularly relates to an economically and technically feasible process for the preparation of p-methoxy phenylacetic acid from p-methoxy acetophenone using sulphur ammonia as reagents and isopropyialcohol as solvent dispensing the use of morpholine as amine for Willgerodt - Kindler reagents. The p-methoxy phenyl acetamide after purification by crystallization was hydrolyzed in a base at refluxed temperature. The crude phenylacetetic acid obtained after workup was extracted into hot water, followed by recrystallisation from toluene there by making the process more economical and convenient yielding the pure product. p-Methoxy phenylacetic acid is a versatile intermediate used extensively in synthetic orqanic chemistry. Arylalkanoic acids are used predominantly as building blocks for the production of , such as dextromethorphan, anti-cough medicine; homoveratric acid, obtained from 3,4 dimethoxy acetophenone (DMAP) is an importantant pharmaceutical intermidiate; 4-phenyl phenylacetic acid an analagesic is produced from 4-phenyl acetophenone and are showing broad range of biological activity i.e., antibacterial, anlagesic, virucida, prostaglandin synthetase response, plant growth regulator]. It is used as an additive in the manufacture of (un)substituted indigo dyes. It is also used as corrosion inhibitor for aluminum in acidic and alkaline solution. Extensive literature search reveals that the preparation of Arylalkanoic acids from thioamide proceeds via Willgerodt -Kindler reaction. The thioamide can be synthesied by reacting an aryl alkanoic ketone or other starting material, sulphur and primary or secondary amine following the preparation of thioamide which can be hydrolyzed to the corresponding alkanoic acid. The Willgerodt reaction is well documented reaction between an aryl alkanoic ketone and aq. ammonium polysulphide to produce an aromatic amide or ammonium salt of the corresponding acid. It is also applicable for the production of amide for other compounds such as dialkyl ketone, alphatic mercaptain, secondary and tertiary alcohol, acetals, and aromtic hydrocarbon. A mixture of sulphur and ammonia is known to be equivalent to ammonium polysulphide in obtaining the reaction. Kindler's modification to the Willgerodt reaction indicated the use of an aryl alkanoic ketone, which can be heated with sulphur and primary, secondary amine such as morpholine and the product is thiomorpholide. Refernce may be made to J. Sci. Ind. Res., 21B, 1962, 284-5 which reports a method for the preparation of arylacetic acid from the arylalkyl ketone by modification of Willgerodt -Kindler reaction involving the use of morpholine and sulphur and reflux with ketone followed by basification, cooling, filtration and acidification. However this process does not indicate the use of sulphur removal technique. Refernce may be made to U. S. patent No. 2,489,348 issued Nov. 29, 1949 which reports the preparation aryl acetic acid and amide. Some examples reveal the purification of crude acid by basification, filtering and acidification to yield the free acid. This method does not indicate the use of sulphur nor function like Willgerodt- Kindler reaction. Reference may be made to U.S. Patent 2,459,706,1949 wherein the production of amides is realized by reacting aliphatic mercaptans, ammonia or amine with ammonium polysulphide or sulphur in secondary or tetairy alcohol via Willgerodt reaction. Reference may be made to U.S. Patent No. 2,572,809,1951 wherein the Willgerodt reaction between acetal and ammonium polysulphide or ammonium hydroxide and sulphur in aq. System, secondary or primary amine and sulphur in anhydrous system to produce amides. Reference may be made to U.S.Patent 2,610,980, 1952 discloses the formation of amide by reacting aromatic hydrocarbon with ammonium polysulphide or sulphur and ammonia in the presence of water as well as under anhydrous conditions. Reference may be made to U.S. Patent No.2,689,246,1954 indicates the Willgerodt reaction of unsaturated nitro compounds with ammonium polysulphide or ammonia or an amine and sulphur in aq. system for a carboxylic acid amine or an anhydrous system to form the corresponding thioamide. Reference may be made to German Patent No. 405,675 ,1924 reports the preparation of thioamide by reacting aldehyde or ketone with ammonia, primary or seconday amine with sulphur. However the only specific example utilizing ammonia gas , benzaldehyde is reacted to form thiobenzamide, Reference may be made to "The Willgerodt Reaction " synthesis 1975, p. 358 wherein reports the Willgerodt reaction of various aryl methyl ketones and other compounds with ammonium polysulphide or suphur and ammonium hydroxide in an aq. system to produce aryl acetamide or sulphur and amine such as morpholine in Willgerodt-Kindler reaction to produce thioamide. Reference may be made to "The willgerodt reaction " Vol.111 ,1946, 83 reports the Willgerodt reaction of several aryl ketones with ammonium polysulphide or sulphur and aq. ammonia to produce aromatic acetamide and also shows example of the Kindler modification involve the reaction any of various methyl aryl ketones with sulphur and amine in an anhydrous system to produce acetothioamide. Reference may be made to J. Amer. Chem. Soc. 68, 1946, 2633 describe the preparation of p-hydroxy phenyl acetamide by Willgerodt reaction of p-hydroxy acetophenone and ammonium sulphide in an aq. System. The main objective of the present invention is to develop an alternative, efficient, eco-nomical technology for the synthesis of p-methoxy phenylacetic acid from p-methoxy acetophenone by reacting p-methoxy acetophenone with sulphur in alcoholic ammonia by Willgrodt reaction. In order to achieve this goal, the process was developed using ammonia as amine in the Willgerodt reaction under pressure and elevated temperature in alcoholic media. In compliance with this objective the present invention describes a convenient approach to the desired synthesis of p-methoxy phenylacetic acid utilizing ammonia as amine, which is commercially available at affordable price. Summary of the invention: The interesting improvement of the invention lies in the use of commercially available ammonia in isopropyl alcohol as medium wherein p-methoxy actophenone and sulphur are reacted under pressure and elevated temperature to yield the amide which on hydrolysis in base followed by work up to yield crude p-methoxy phenylacetic acid which was further purified by extraction into hot water and subsequent crystallized from toluene. This invention offers good yield, technically feasible and economically viable. These advantages are quite an impivssing. when compared with the process currently practiced utilizing expensive and non-recoverable morpholine reagent. Detailed description of the invention: Accordingly, the present invention relates to an improved process for the prcpartion of p-substituted phenylacetic acid from p-substituted acetophenone which comprises of following steps: a. reacting a p-methoxy acetophenone with sulphur 6 mol and ammonia gasl 4 mol. is employed in amount in the presence of isopropanol as solvent at temperatiution the range of 100-145°C for a period of 8-10 hrs. b. cooling the reaction mixture to 60-65°C and passing through the sodium hydroxide scrubber (10%, 2.5 Lit) and then cooled to -10°C to obtain phenyl acetamide; c. suspending the above said phenyl acetamide 1.30 moles in about I5° solroer of sodium hydroxide 5.88 moles; d. heating the rection mixture slowly to 80°C -110°C under stirring and aller hydrolysis ,cooling the reaction mixture moderately to 45°C -50°C and filtering off the insolublcs .polymeric materials; e. cooling the filtrate further to room temperature and acidified using 30-35° HC'L acid to pH 6 and filtered again to remove any solid effluent; f. cooling the filtrate obtained to 5°C and acidified again using 30-35%HCL acid to obtained crude p-methoxy phenyllacetic acid (75%); g. the above said crude p-methoxy phenyllacetic acid extracted with water at W°C and cooled to 5°C to obtain white crystals of p-methoxy phenyllacetic acid further purified by crystallization from toluene and obtained pure alpha phenylacetic acid 55%. In one of the embodiment of the present invention, the amine representing ammonia, is employed in amount such as 6-7mol% with respect to the substrate to obtain highest selectivity of the desired product. In another embodiment of the present invention, the solvent represents isopropyl alcohol that is isopropyl alcohol recovered from previous experiment and re-used in the process without further purification and treatment. In yet another embodiment of the present invention, the reaction is affected at a temperature preferably in the range of 140-145°C for 8-9 hrs. In still another embodiment of the present invention, the crude product of p-substituted phenylacetic acid is extracted with hot water to obtain pure product free from sulfur and in-situ formed sulfide. In further embodiment of the present invention, A process as claimed in claims 1-5, wherein the product p-substituted phenylacetic acid finally purified from toluene. In yet further embodiment of the present invention, the improvement comprising the employment of ammonia as amine substantially reduces difficulties pertaining to process operation for the recovery of amine such as morpholine. In yet further embodiment of the present invention, the improvement comprising the employment of ammonia as amine makes the process more viable and economical. In still further embodiment of the present invention, the improvement resulting from the method of claims 6&7 offers convenience and eliminates steps of purification such as high vacuum distillation. Scientific Explanation The use of morpholine for Willgerodt reaction posed serious problem of recovering the morpholine. The use of dimethyl amine as amine for Willgerodt reaction did not add any advantage either economically or technically and thus made the.process more un-economical by using other amines. The use of ammonia is proved to be the best in terms of economics of the process. The use of sulphur leads to the formation of H2S, which was well protected, from the environment by using the autoclave under pressure followed by digesting the effluent with an appropriate scrubber and thus to make the process more ecofriendly and technically feasible. The formed amide was purified from impurities like colour and polymeric material by crystallization from alcohol used as medium for the reaction. Initially the crude target product obtained after hydrolysis has been purified from the unreacted sulphur and insitu formed suifides by extracting into water instead of using organic solvents for the same and finally by crystallization from toluene made the process more economical, simple and viable. Finally, this invention also explores the reusability of the solvent isopropyl alcohol, recovered from the reaction mixture, without further purification. Thus, the invented strategy offers an economical, simple and viable process for the synthesis of p-methoxy phenyl acetic acid from p-methoxy acetophenone in a batch process. The invention is described in the examples given below which are produced by way of illustrations only and therefore should not be constrained to limit the scope of the invention. EXAMPLE 1: Reagents used are purified as follows: Isopropyl alcohol freshly distilled, Sulphur and ammonia gas are used as commercially available grade. 4-methoxy acetophenone in an amount of 300 g (2 mol.), sulfur in an amount of 192 g (6 mol) and isopropanol in an amount 1700 g saturated with ammonia gas (238 g ,14 mol) at -5°C were charged into a 5 lit titanium autoclave. The autoclave was sealed. The reaction mixture was heated to 140 °C under vigorous stirring and continued the stirring for 8hrs at 140 °C during which time the autogenous pressure in the autoclave rose from 15 psig upto 250 psig at the end of reaction. The reaction mixture was cooled to 60-65°C and slowly digested the effluent gas by passing through the sodium hydroxide scrubber (10%, 2.5 lit.) to minimize the effluent generated during the reaction. The mixture was discharged from the reactor and then cooled to -10 °C and obtained the crystalline phenyl acetamide in 65% after filtration and drying in air. The phenyl acetamide 215 g(1.30 moles), was suspended in 15 % solution of sodium hydroxide 235 g.(5.88 moles). The reaction mixture was heated slowly to102°C under stirring. After hydrolysis, the reaction mixture was moderately cooled to 45 to 50°Cand filtered off the insolubles, polymeric materials. The filtrate was further cooled to room temperature and acidified using 30-35% HCI acid 450g to pH 6 and filtered again to remove any solid effluent. The filtrate obtained at pH 6 was cooled 5°C and acidified again using 30-35 % HCI acid 55 g to pH 4 to obtained crude p-methoxy phenylacetic acid 249g (75%). The crude phenyl acetic 100 g was extracted into hot water 1000ml at 90°C. The water extract was cooled to 5°C and obtained white crystals of p-methoxy phenylacetic acid which was further purified by crystallization from 500 ml toluene and obtained pure apha white crystals of phenylacetic acid 55%. EXAMPLE 2: Following the standard procedure as above and utilizing the following amounts of reagents: Acetophenone 240g,(2moles), sulphur 192g(6moles), isopropanol 1700 g, ammonia gas (238 g 14 mol),for hydrolysis sodium hydroxide 235 g.(5.88 moles),30-35% HCI acid 505 g. afforded pure(>99) phenylacetic acid (177g, 65% yield). EXAMPLE 3: following the standard procedure as above and utilizing the following amounts of reagents: p-Chloro acetophenone 308g,(2moles), sulphur 192g(moles), isopropanol 1700 g, ammonia gas 238 g ,14 mol),for hydrolysis sodium hydroxide 235 g.(5.88 moles),30-35% HCI acid 505 g. aff'orded pure(>99) p-Chloro phenylacetic acid (204g 60% yield). EXAMPLE 4: Following the standard procedure as above and utilizing the following amounts of reagents: p-hydroxy acetophenone 272g,(2moles), sulphur 192g(moles), isopropanol 1700 g, ammonia gas (238 g ,14 mol),for hydrolysis sodium hydroxide 235 g.(5.88 moles),30-35% HCI acid 505 g. afforded pure(>99) p-hydroxy phenylacetic acid (152g 50% yield). EXAMPLE 5: The solvent isopropyl alcohol, recovered from the first experiment (Example 1), is used here without further purification. All other reagents are purified as described earlier. Following the standard procedure as above and utilizing the following amounts of: p-methoxy acetophenone 300g, (2.0moles), sulphur 192g(6.0moles), isopropanol 1700 g, ammonia gas (238 g ,14 mol), for hydrolysis sodium hydroxide 235 g.(5.88 moles),30-35% HCI acid 505 g. afforded pure(>99%) p-methoxy phenylacetic acid (182g 55% yield). The present process has several advantages as described below: 1 The process is economically and technically feasible. 2. The process eliminates the use of water soluble and costly recovery of amine, morpholine. 3. Ammonia used, as amine in place of morpholine, is cheap, abundantly available and also can be made economically. 3. The selectivity and the product yield are as good as in the morpholine used reaction. 5. The reaction is simple with shorter duration and the work-up procedure being simple makes the process more economical. 6. The present process involving the use of sulfur and ammonia envisages no problem of hfeS and other effluent pollution by using alkaline scrubber. 7. The present process is more safer than the process wherein the use of cyanide or carbon monoxide are inevitable. We claims: 1. An improved process for the preparation of p-substituted phenylacetic acid from p-substituted acetophenone which comprises of following steps: a. reacting a p-methoxy acetophenone with sulphur 6mol and ammonia gas 14 mol, is employed in amount in the presence of isopropanol as solvent at temperature in the range of 100-145°C for a period of 8-10 hrs. b. cooling the reaction mixture to 60-65° C and passing through the sodium hydroxide scrubber (10%, 2.5 Lit) and then cooled to -10 C to obtain phenyl acetamide; c. suspending the above said phenyl acetamide 1.30moles in about 15% solution of sodium hydroxide 5.88moles; d. heating the rection mixture slowly to 80° C -110° C under stirring and after hydrolysis ,cooling the reaction mixture moderately to 45° C -50 C and filtering off the insolubles ,polymeric materials; e. cooling the filtrate further to room temperature and acidified using 30- 35% HCL acid to pH 6 and filtered again to remove any solid effluent. f. cooling the filtrate obtained to 5°C and acidified again using 30-35% HCL acid to obtained crude p-methoxy phenyllacetic acid (75%); g. the above said crude p-methoxy phenyllacetic acid extracted with water at 90°C and cooled to 5°C to obtain white crystals of p-methoxy phenyllacetic acid further purified by crystallization from toluene and obtained pure alpha phenylacetic acid 55%. 2. A process as claimed in claim 1, wherein the reaction is affected at a temperature preferably in the range of 140-145° C. 3. A process as claimed in claim 1, wherein the reaction is preferably done for a period 8-9 hrs. 4. An improved process for the preparation of p-substituted phenylacetic acid from p-substituted acetophenone substantially as herein described with to refrences to examples accompanying the specification.

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533-del-2003-abstract.pdf

533-DEL-2003-Claims-(28-11-2008).pdf

533-del-2003-claims.pdf

533-DEL-2003-Correspondence-Others-(28-11-2008).pdf

533-del-2003-correspondence-others.pdf

533-del-2003-correspondence-po.pdf

533-DEL-2003-Description (Complete)-(28-11-2008).pdf

533-del-2003-description (complete).pdf

533-del-2003-form-1.pdf

533-del-2003-form-18.pdf

533-del-2003-form-2.pdf

533-DEL-2003-Form-3-(28-11-2008).pdf

533-del-2003-form-3.pdf