AN IMPROVED PROCESS FOR THE PREPARATION OF 5- AMINO-2-HYDROXY BENZOIC ACID (MESALAMINE)
FIELD OF THE INVENTION
This invention relates to one-pot process for the preparation of 5- Aminos-Hydroxy Benzoic acid commonly known as Mesalamine, which is being used as an effective anti -inflammatory (Gastro intestinal) drug.
BACK GROUND OF THE PRIOR ART
Mesalamine having the structural formula I is a known anti-inflammatory drug and is reported to produce by the following synthetic strategies:
In the patent JP 6340600 disclosed in Japan, the aniline process uses aniline as a starting material to obtain an aniline diazonium salt, which is then coupled with salicylic acid, and then the azo bond is cleaved by reduction to obtain one molecule of 5-ASA while removing another molecule of aniline (see reaction (1) below). Moreover, in another literature (Zhu Zhi-qing et al., Preparation of mesalamine by catalytic hydrogenolysis, Chinese Journal of Pharmaceuticals, 1999, 30(1):8 9), the azo bond is reduced by hydrogen gas using Raney-Ni as catalyst, to obtain 5-ASA (see reaction (2) below), and the yield of this route reported by the literature is no more than 50%. Although the method is easy to operate, it is not suitable for the production because the process route is long, and aniline and azo compounds are toxic, and are environmentally hazardous to some extent, and are easily introduced into the final product by raw materials, thus seriously affect the purity of the product and thereby resulting in increased costs for the purification.
The synthetic route of this process is shown in scheme 1 & la:

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 forgetting a product of pharmaceutical purity. Scheme-2
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 diazohium salt of aniline (X=H) or sulphanilic acid (X = SO2NH2) to form a diazo intermediate compound of Formula II (X = H or S02NH2) which is then reduced to 5-aminosalicylic acid (Scheme 3). 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, [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.
US 4670112, 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.
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 one-pot process for preparation of 5-Amino-2-Hydroxy Benzoic acid which involves reaction of 2-halo-5-nitrobenzoic acid in presence of a base and in presence or absence of a solvent at elevated temperature.
In a preferred embodiment of the present invention, process for preparation of 5-Amino-2-Hydroxy Benzoic acid which involves reaction of 2-halo-5-nitrobenzoic acid in presence of bases at temperature ranges from about 100 to 150° C to form 5-aminosalicylic acid.
In another embodiment of the invention, process for preparation of 5-Amino-2-Hydroxy Benzoic acid which involves reaction of 2-halo-5-nitrobenzoic acid, halo represents cloro, bromo, floro and iodo. Preferably 2-chloro-5-nitrobenzoic acid in presence of bases at temperature ranges from about 125 to 130° C and addition of metal catalyst at ambient temperature is used for the reduction of nitro intermediate which was formed insitu.
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 one-pot process for the preparation of p-aminophenols especially 5-Amino-2-Hydroxy Benzoic acid of formula-I using 2-halo-5-nitrobenzoic acid of formula III as a key raw material in the presence of base and the reaction temperature ranges from about 100° C to about 150° C.

According to present invention, process for the preparation of especially 5-Amino-2-Hydroxy Benzoic acid of formula-I using key raw material 2-halo-5-nitrobenzoic acid where in halo represents cloro, bromo, fluoro and iodo group, preferably 2-chloro-5-nitrobenzoic acid of formula III in the presence of base. Process has the advantage of minimal or no usage of of solvent system which in turn reduces the cost of the reaction. The reaction temperature ranges from about 100° C to about 150° C. Preferably from 125° C to about 130° C for reaction time of 5 hrs.
The base advantageously used is alkali metal hydroxides. Alkali metal hydroxides include is sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, or calcium hydride. Preferably potassium hydroxide.
Salt of 2-hydroxy-5-nitrobenzoic of formula-II 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.
In the process of the present invention, metal catalysts are screened out with good catalytic performance is charged in to the reaction mass while pH of 7 to 8 is maintained inside of the autoclave. Metal catalyst charged in the reaction mass is raney nickel, palladium carbon, platinum catalyst adsorbed on activated charcoal or aluminum. Preferably palladium carbon.
The acid employed in the acidification of this process is sulfuric acid, hydrochloric acid, '
and nitric acid. Preferably hydrochloric acid. The reaction is maintained at temperature ranges from about 20° C to 40° C. Preferably from 30° C to 35° C when charging with metal catalyst and acid. The autoclave is purged with hydrogen gas to maintain the pressure to about 3 to 10 kg / inch, preferably 6 kg / inch. The reaction mass is heated gradually to about 50 to 80 °G, preferably 60 to 65 °C and then maintained for 8 to 10 hours. The reaction completes in a time span of 12 to 14 hours under 6 kg / inch pressure and 60° C to 65° C temperature. The precipitated product on cooling is filtered off and pH adjusted to 3 to 3.5 with sodium bicarbonate solution at 30 - 35° C to precipitate pure 5-aminosalicylic acid.

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The following specific examples are presented to illustrate the invention but are not limited to the specific embodiments presented herein.
Example 1
Preparation of Mesalamine:
A mixture of water (500ml) and potassium hydroxide (140 gm) was stirred in an autoclave and 2-Chloro-5-Nitro benzoic acid (lOOgm) was charged to it, heated to about 120-125°C and maintained for 6 hrs. Reaction was checked by using thin layer chromatography, cooled to 25-35°C and pH was adjusted to 7-8. 5% palladium carbon (4gm) was charged into reaction mass. Reaction mass was heated to about 60-65 C and maintained for 7hrs. After completion of the reaction, contents were cooled to 25-35°C. Filtered the contents through hyflo bed and washed with water. Sodium metabisulphate (lOgm) was charged to the filtrate and stirred for 30mins at 25-35°C, Adjusted pH of the solution 3.0-3.5 with hydrochloric acid and stirred for lhr. Solid was filtered and washed the product with water. Sucked dry the material for lhr. This wet compound was stirred with water (l.Olt). Hydrochloric acid was slowly added until clear solution was attained and carbon was charged into it and stirred for 30mins and filtered through hyflow bed and washed with water. Sodium carbonate was added and pH was adjusted to 3.0-3.5 with solution and solid was obtained. Reaction mass was stirred for 30 minutes and filtered and washed with water and dried at 70-75°C for 12hr, which yielded 65g of mesalamine (Yield 85%) with Purity by HPLC: > 99.0%

Example 2
Preparation of Mesalamine:
Potassium Hydroxide (140g) was dissolved in water (500ml) in an autoclave and charged with 2-Chloro-5-Nitro benzoic acid (lOOg) and maintained at ambient temperature for 6hrs, cooled to 25-350C and pH was maintained at 7 to 8. 5% palladium carbon was added to the reaction mass and maintained the reaction with 6kg pressure at 550C for 6 . hrs and cooled to 25-350C. Filtered the contents through hyflo bed and pH was adjusted to 3.0 to 4.0 with dilute hydrochloric acid. The wet compound was dissolved in 1.5 liters of water; dilute hydrochloric acid was added until clear solution was attained and then was charged with carbon and heated to ambient temperature and filtered through hyflo bed. Adjusted the pH of the filtrate to 3.0-4.0 with sodium carbonate solution and solid was isolated. Maintained for 30 minutes and mesalamine was filtered, washed and dried at about 700C for 12hours, which yielded 55g (Yield72.3%) with purity by HPLC: 98%.

We claim,
1. One-pot process for preparation of 5-amino-2-hydroxybenzoic acid of Formula I comprising:
a) Reacting 2-halo-5-nitrobenzoic acid of Formula (HI) in presence of a base and the reaction is carried out in temperature for 5 to 6 hours,
b) Adding metal catalyst to the reaction mass and maintaining the temperature under pressure,
C) Isolating 5-amino-2-hydroxybenzoic acid of formula I from said reaction mass.
2. The process according to claim 1, wherein said process is carried out in the
absence of solvent.
3. The process according to claim 1 step a, wherein the basic compound is sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, or calcium hydride thereof.
4. The process according to claim 4, wherein the basic compound is potassium hydroxide.
5. The process according to claim 1 wherein said step a, the reaction is carried out at a temperature ranging from about 100 to 150°C. Preferably 125° C to about 130° C.
6. The process according to claim 1 step a, wherein pH of the autoclave is maintained at 7 to 8.
7. The process according to claim 1 step b, wherein the metal catalyst is raney nickel, platinum catalyst adsorbed on activated charcoal/aluminum, palladium carbon thereof
8. The process according to claim 7, wherein the metal catalyst is palladium carbon.
9. The process according to claim 1 step b, wherein said pressure for effecting complete reaction is ranging from about 5 to 10 Kg/inch at a temperature of 60 to 65 °C.
10. A process for preparation of 5-amino-2-hydroxybenzoic acid as substantially described herein with reference to the foregoing examples 1 and 2.