Title of Invention	ONE - POT PROCESS FOR THE PREPARATION OF 5-AMINO -2HYDROXY BENZOIC ACID (MESALAMINE)
Abstract	Disclosed herein is a one-pot regilselective process for preparation of 5-amino-2-hydroxybenzoic acid, which comprises a reaction of paracetamol with carbondioxide in presence of a base, and in presence or absence of a solvent under pressure at higher temperature.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; Rule 13] "One-pot process for the preparation of 5- Amino-2-Hydroxy Benzoic acid (Mesalamine)" (a) IPCA LABORATORIES LIMITED (b) 48, Kandivli Industrial Estate, Mumbai - 400 667, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of this invention and the manner in which it is to be performed: GRANTED 18-11-2004 1242 /MUM / 2004 18 NOV 2004 Field of Invention This invention relates to one-pot process for prepartion of 5- Amino-2-Hydroxy Benzoic acid commonly known as Mesalamine, which is being used as an effective anti -inflammatory (Gastro intestinal) drug. Back ground of prior art Mesalamine having the structural formula I is a known anti-inflammatory drug and is reported to produce by the following synthetic strategies: NH2 Formula I Chinese patent No. CN1053229 published in 1991 discloses a process by nitrating the salicylic acid and then reducing the nitro group of the resulting intermediate to form 5-aminosalicylic acid (Scheme 1). This method suffers from the impurity formed by the substitution at the 3-position, which needed additional purification and thereby considerable yield losses for getting a product of pharmaceutical purity. Another report, [RU 2155746, Huazhong Keiji Daxue Xuebao, Yixueban - 2002, 31(2), 163-164] provides a regio-selective method for the amine substitution at 5-position of salicylic acid involving a diazocoupling reaction. This process involves reaction of salicylic acid with diazonium salt of aniline (X=H) or sulphanilic acid (X = S02NH2) to form a diazo intermediate compound of Formula II (X = H or SO2NH2) which is then reduced to 5-aminosalicylic acid (Scheme 2). The reduction is performed by either using dithionite or analogous sulfur compound or hydrogenation catalysts such as palladium or platinum or electrolitical hydrogenation. Apart from the use of hazardous sulphur reagents in the hydrogenation, the process involves many number of stages/operation, not suitable from an industrial point of view. In yet another report (Ref. Hoechst, D.R.P. 96853) 5-aminosalicylic acid was prepared from nitro benzoic acid by partially reducing it to hydroxylamine derivative and then rearranging the hydroxylamine to 5-Amino-2-Hydroxy Benzoic acid in acidic medium. However, this method suffers from problems in practical utilization like incomplete transformation of hydroxylamine intermediate to 5- Amino-2-Hydroxy Benzoic acid and regio-selectivity thereby isomeric impurity formation, which is difficult to get rid off. Scheme 3 In yet another report, [Zhaongguo Yiyao Gongye Zazh , 1997, 28(8), 341-342], 5-Amino-2-Hydroxy Benzoic acid was prepared from para- amino phenol by reacting it with carbon dioxide under pressure (Scheme 4). This process also leads to isomeric impurity formation due to the high activating character of amino group. US4670112, discloses a method for preparation of 5-aminosalicylic acid by preparing 5-phenolazosalicylic acid followed by electrolytic reduction. The above mentioned methods for preparing 5-Amino-2-Hydroxy Benzoic acid suffer from various shortcomings. Either the reaction produces undesirable isomers resulting in low yield or the process uses toxic and hazardous chemicals which pollute the environment, or the process requires handling of air and light sensitive chemicals such as para-aminophenol which catches color and develops impurities on exposure to light and air. Also most of the processes described above involve more than one synthetic step/operation. Objective of the present invention It is an objective of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art or to provide a useful alternative. It is an object of the present invention in its preferred form to provide a simple, plant friendly one-pot process for preparation of 5- Amino-2-Hydroxy Benzoic acid which does not require handling of toxic and hazardous chemicals or specialized equipment. Summary of the invention Accordingly, the present invention discloses a one-pot process for preparation of 5-Amino-2-Hydroxy Benzoic acid which involves reaction of paracetamol (4-hydroxyacetanilide) with carbon dioxide in presence of a base and in presence or absence of a solvent at elevated temperature. In a preferred embodiment of the present invention, paracetamol and potassium carbonate are heated in a carbondioxide atmosphere at temperature ranges from about 150 to 250° C to form 5-aminosalicylic acid. In another embodiment of the invention, paracetamol and potassium carbonate in a high boiling solvent like diphenyl ether are heated in presence of sufficient carbondioxide at a temperature ranges from about 150 to 250° C to form 5-aminosalicylic acid (5-Amino-2-Hydroxy Benzoic acid). The product is isolated by an aqueous work-up involving addition of water and precipitation of 5- Amino-2-Hydroxy Benzoic acid by neutralization/acidification. Detailed Description The present invention describes electrophilic substitution of carbon dioxide to an acetyl protected 4-aminophenol. The direct substitution of carbon dioxide on to 4-aminophenol yields to isomers namely 2- and 3- substituted isomers wherein 2 is the desired product. This might be due to the activation of the benzene ring by the amino group. The use of a rather commercial reagent like paracetamol has advantages that the activation of the benzene ring is reduced by acetylation of amino group and is stable to air and light. According to present invention, a regio-selective substitution of p-hydroxy acetanilide with carbon dioxide in presence of base and the deprotection of the amino group of the resulting intermediate can be accomplished in situ or one-pot manner, which has many advantages on an industrial scale for production of 5-aminosalicylic acid. The base advantageously used is alkali metal carbonates or hydroxides. Alkali metal carbonates are anhydrous potassium carbonate or sodium carbonate and alkali metal hydroxides include potassium hydroxide and sodium hydroxide. The molar amount of base used is in the range of about 1 to 4 moles relative to the starting paracetamol and preferably in the range of about 2 to 2.5 moles. The reaction is accomplished under neat condition or in presence of a solvent at elevated temperature. The solvent is selected from high boiling solvents like diphenyl ether. The reaction temperature ranges from about 150° C to about 250° C and pressure ranges from 10 to 50 kg / inch2. The preferable reaction temperature is in the range of about 195° C to 205° C at a pressure of 25 to 35 kg / inch2. In the process of the present invention, paracetamol is intensely mixed with anhydrous potassium carbonate in a pressure reaction vessel/autoclave. The autoclave is charged with carbon dioxide till a pressure of about 10 to 50 kg / inch2, preferably 25 to 35 kg / inch2 is reached. Thereafter the reaction mass is heated gradually to about 150° C to 250° C, preferably about 195 to 205° C. The reaction completes in a time span of 10 to 24 hours, preferably 12 to 14 hours. The product was then hydrolyzed in the same vessel by addition of water at 10- 15° C and isolated by acidification with concentrated hydrochloric acid. The pH on acidification is in the range of about 4 to 5.5 and preferably in the range of pH 4.0 to 4,5, for better purity and yield. In another process variant, the reaction is carried out in presence of a solvent like diphenyl ether, which improves the fluidity of the reaction mass. Accordingly, in the process, a solvent medium in the ratio of 2 to 8 weight by volume of paracetamol, preferably 4-5 weight by volume is charged in an autoclave followed by a mixture of paracetamol and anhydrous potassium. The autoclave is charged with carbon dioxide to take the pressure to about 10 to 50 kg / inch2, preferably 25 to 30 kg / inch2. The reaction mass is heated gradually to about 150° to 250 °C, preferably 195° to 205°C and then maintained for 10 to 24 hours. The reaction completes in a time span of 12 to 14 hours under 25 to 30 kg / inch2 pressure and 195° C to 205° C temperature. The precipitated product on cooling is filtered off and the wet product is purified by washing with toluene to remove high boiling solvent medium. The obtained residue is then dissolved in water, cooled to 10- 15° C and pH adjusted to 4.2 with concentrated hydrochloric acid to precipitate pure 5-aminosalicylic acid. The following specific examples are presented to illustrate the invention but are not limited to the specific embodiments presented herein. Example 1 A mixture of finely powdered 50.0 gm of paracetamol and 114.0 gm of finely grounded calcined anhydrous Potassium carbonate was charged in a 500 ml autoclave. This was flushed twice with carbon dioxide gas and a pressure of 25 kg / inch2 taken with carbondioxide and heated to 40° C and maintained for two hours. The temperature was then raised to 200° C and heating continued for twelve hours. After the reaction was completed the powdered product was dissolved in 500 ml water, cooled to 10°C -15 ° C and concentrated hydrochloric acid was added until a pH of 4.2 attained. The precipitated 5- Amino-2-Hydroxy Benzoic acid was filtered off, washed with water and dried to constant weight. Example 2 A mixture of finely powdered 15.0 gm of paracetamol, 38.0 gm of finely grounded calcined anhydrous Potassium carbonate and 75.0 ml of diphenyl oxide was charged in a 500 ml autoclave. The mixture was flushed twice with carbon dioxide gas and a pressure of 25 kg / inch2 was taken with carbon dioxide and heated to about 200° C, maintained heating for twelve hours. After reaction was complete the precipitate was filtered and washed with 25 ml toluene. The wet cake was dissolved in 130 ml water and then cooled to 10° C-15° C and concentrated hydrochloric acid was added until a pH of 4.2 attained. The precipitated 5- Amino-2-Hydroxy Benzoic acid was filtered off, washed with water and dried to constant weight. While we have described our preferred embodiments in the examples here, varieties on this disclosure can be discerned by one of skilled in the art. Thus we intend the legal coverage of our patent to be defined not by the specification and examples, but the appended claims. We claim, 1. One-pot process for preparation of 5-amino-2-hydroxybenzoic acid of Formula I comprising: reacting paracetamol (p-hydroxy acetanilide) of Formula (II) with carbon dioxide in presence of a base under pressure to form a reacti«h mass containing 5-amino-2-hydroxybenzoic acid; and isolating 5-amino-2-hydroxybenzoic acid of formula (I) from said reaction mass. Formula I Formula II 2. The process according to claim 1, wherein said process is carried out in the presence or absence of solvent. 3. The process according to claim 1 or 2 wherein said reaction is carried out at a temperature ranging from about 150 to 250°C under pressure. 4. The process according to any one of the preceding claims wherein said pressure for effecting complete reaction is ranging from about 15 to 50 Kg/inch2 at a temperature of 150 to 250°C. 5. The process according to any one of the preceding claim, wherein said base is selected from alkali-metal carbonates or alkali-metal hydroxides. 6. The process according to claim 5, wherein said alkali metal carbonate is potassium carbonate or sodium carbonate. 7. The process according to claim 5, wherein said alkali metal hydroxide is potassium hydroxide or sodium hydroxide. 8. The process according to claim 2, wherein the said solvent is selected form high boiling solvents. 9. The process according to claim 8 wherein said solvent is diphenyl ether. 10. The process according to any one of the preceding claim wherein said reaction temperature is 195 ° C to 205° C at a pressure of 25 to 35 kg / inch2. 11. The process according to any one of the preceding claims, wherein said reaction of paracetamol with carbon dioxide and isolation of 5-amino-2-hydroxy benzoic acid are carried out in a singe-pot. 12. A process for preparation of 5-amino-2-hydroxybenzoic acid as substantially described herein with reference to the foregoing examples 1 and 2. Dated this the day of 18th Nov 2004 Dr. Gopakumar G. Nair Agent for the Applicant

Documents:

1242-mum-2004-abstract(18-11-2004).doc

1242-mum-2004-abstract(18-11-2004).pdf

1242-mum-2004-claims(granted)-(18-11-2004).doc

1242-mum-2004-claims(granted)-(18-11-2004).pdf

1242-mum-2004-correspondence(05-09-2007).pdf

1242-mum-2004-correspondence(ipo)-(13-08-2007).pdf

1242-mum-2004-form 1(18-11-2004).pdf

1242-mum-2004-form 18(02-11-2006).pdf

1242-mum-2004-form 2(granted)-(18-11-2004).doc

1242-mum-2004-form 2(granted)-(18-11-2004).pdf

1242-mum-2004-form 26(18-11-2004).pdf

1242-mum-2004-form 3(18-11-2004).pdf