FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Balsalazide of Formula I,

BACKGROUND OF THE INVENTION
5-(lE)-[[4-[[2-Carboxyethyl)amino]carbonyl]phenyl]azo]-2-hydroxybenzoic acid is generically known as Balsalazide. Its disodium salt dihydrate, which is generically known as Balsalazide disodium dihydrate is marketed under the trade name COLAZOL. Balsalazide is an anti-inflammatory (gastrointestinal) drug useful as a medicament for the treatment of disease such as ulcerative colitis. It is delivered intact to the colon where it is cleaved by bacterial azoreduction thereby generating 5-amino salicyclic acid (Mesylamine) as the medicinally active compound.
Balsalazide disodium dihydrate was first disclosed in US 4,412,992. The anti¬inflammatory (gastrointestinal) activity of balsalazide has been reported in several publications eg, Arzeneim-forsch/Drug 48(ll)Nr.l2 (1998),
The process to prepare Balsalazide disodium dihydrate according to US 4,412,992, involves converting 4-nitrobenzoyl chloride to 4-nitrobenzoyl-βalanine and hydrogenating with Pd/C (5%) in ethanol / diethyl ether to produce 4-aminobenzoyl-β-alanine. Thereafter, 4-aminobenzoyl-β-alanine was treated with hydrochloric acid and sodium nitrite to generate N-(4-diazoniumbenzoyl)-β-alanine hydrochloride salt

which was reacted at low temperature with disodium salicylate to furnish Balsalazide disodium insitu which was added to dilute hydrochloric acid at low temperature to produce Balsalazide, Thus obtained Balsalazide was recrystallized with hot ethanol and converted to pharmaceutically acceptable salt (disodium salt). This is depicted in following scheme.

Hydrogenation involves the use of diethyl ether, higher volume of ethanol (--14 times) and a large quantity of palladium on charcoal catalyst. This patent also does not mention any pH for the isolation of Balsalazide. Filterability of the reaction mass is very poor and takes longer time during filteration. Moreover formation of more impurities has also been observed. These impurities could not be removed by recrystallization from ethanol. Further, higher volumes of ethanol were required to solubilise Balsalazide owing to its poor solubility in ethanol.
Thus, there remains a need for a cost effective, safe and industrially feasible route to manufacture Balsalazide disodium.
OBJECTIVE
The objective of the present invention is to provide an improved process for preparing pure Balsalazide disodium, with high yields and high purity.

Another objective of the present invention is to provide an improved process for preparing pure Balsalazide disodium, which is industrially feasible and economically viable.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for preparing Balsalazide of Formula I,

using halogenating agent in an organic solvent to give 4-nitrobenzoyl chloridc, which in situ is reacted with sodium salt of β-alanine in DM water to give 4- nitrobenzoyl-β-alanine of Formula III


li) isolating and suspending the 4-nitrobenzoyl-β-alanine of Formula III in DM water in the presence of a base and hydrogenating to give 4-aminobenzoyl-β-alanine of Formula IV

iii) optionally isolating the 4-aminobenzoyl-β-alanine of Formula IV and diazotizating in DM water, which in situ is reacted with disodiumsalicylate to furnish mixture of Balsalazide of Formula V and its mono sodium salt of Formula VI

with a ratio of 60:40-80:20; iv) optionally purifying the mixture obtained in step iii; and v) converting the mixture in to Balsalazide disodium of Formula I.

DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed towards an improved process to prepare Balsalazide disodium salt of Formula (I), by reacting 4-nitrobenzoic acid with an halogenating agent selected from thionyl chloride, oxalyl chloride in an organic solvent such as toluene, diisopropyl ether, cyclohexane, methylene dichloride, to give 4-nitrobenzoyl chloride, which in situ is reacted with sodium salt of β-alanine in DM water to give 4-nitrobenzoyl-β-alanine of Formula III. 4-Nitrobenzoyl-β-aIanine is suspended in water in the presence of a base and hydrogenated using palladium on carbon, and thereafter treated with an acid to give 4-aminobenzoyI-(3-alanine of Formula IV. The base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide or aqueous ammonia and acid is selected from hydrochloric acid, sulfuric acid, acetic acid.
4-Aminobenzoyl-β-alanine is treated with hydrochloric acid and sodium nitrite to generate N-(4-diazoniumbenzoyl)-β-alanine hydrochloride salt and treated with disodium salicylate to furnish Balsalazide disodium. This is acidified with an acid to pH 4.2-5.0 and stirred at 50-80°C, more preferably at 60"65°C for four hours to give a mixture of Balsalazide and its monosodium salt (sodium content -3.54%, by ion chromatography). Balsalazide and its monosodium salt, thus obtained is treated with sodium carbonate in DM water and disodium salt was precipitated with alcohol, more preferably isopropyl alcohol at 5-35°C to obtain pharmaceutically acceptable salt (disodium salt).
The Balsalazide and monosodium salt mixture obtained in step III is purified using aqueous 1,4-dioxane to yield highly pure Balsalazide acid and its monosodium salt mixture that is ideal for the preparation of disodium salt. Purification occurs when 1,4-dioxane suspension is heated at high temperature at 90-65°C and filtered at

relatively high temperature 60-65oC. Several impurities go into solution by heating at 90-95oC. Structures of some of these are as shown below:



The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.
EXAMPLE-1
PREPARATION OF N- (4-NITROBENZOYL)-fi-ALANINE
To a suspension of 4-nitroben2oic acid (200g, l,20mol) in diisopropyl ether (2000ml), thionyl chloride (164g, 1.38mol) was added followed by N,N" dimethylformamide (4g) at 30-35°C. The contents were heated slowly to reflux at 65°C and stirred at the same temperature to complete the reaction. After completion of reaction, the reaction mass was cooled to 5-10°C, and added to a mixture of β-alanine (127.9g, 1.44mol) in DM water (6000ml) containing sodium hydroxide (127.8g) at 5-15°C maintaining pH>8 and the reaction mass was stirred at this temperature to complete the reaction. After completion, the pH of the reaction mass was adjusted to 1.8 using aqueous hydrochloric acid at 8-12°C and thereafter, product was filtered and washed with precooled water to obtain 4-nitrobenzoylβ-alanine Yield: 271g Chromatographic purity: 99.53 %

EXAMPLE-2
PREPARATION OF N- (4-AMINOBENZOYL)-p-ALANINE
To a suspension of 4-nitrobenzoyl-β-alanine (260g, 1.09mol) in DM water (780ml), sodium carbonate (58g, 0.55mol) was added at 20-25°C and stirred the contents at 20-30°C to obtain a clear solution. The reaction mass was hydrogenated at 20-35°C using 10% w/w Pd/C (5.2g, wet) and at 15-20 Kg pressure. After completion of reaction the reaction mass was filtered under nitrogen atmosphere to remove catalyst. Thereafter, concentrated sulfuric acid (53.53g, 0.55mole) was added to the filtrate at 20-25°C and stirred the reaction mass further at 5-10°C to complete the precipitation. The solids were filtered, washed with water and dried to yield 4-aminobenzoyl-β-alanine. Yield: 202g Chromatographic purity: 99.42 %.(by HPLC)
EXAMPLE-3
PREPARATION OF MIXTURE OF 5-[(lE)-[4-[[(2-CARBOXYETHYL)
AMINO]CARBONYL]-PHENYL]AZO]-2-HYDROXYBENZOIC ACID AND
OF 5-[(lE)-[4-[[(2-CARBOXYETHYL)AMINO]CARBONYL]-
PHENYL]AZO]-2-HYDROXYBENZOIC ACID MONOSODIUM SALT [BALSALAZIDE AND BALSALAZIDE MONOSODIUM SALT MIXTURE]
To a suspension of 4-aminobenzoyl-β-alanine (80g, 0.385mole) in DM water (960ml) concentrated hydrochloric acid (80ml) was added at 20-35°C. The reaction mass was filtered and cooled to 2 to -2°C. Thereafter, added aqueous sodium nitrite solution (27.86g, 0.403mol dissolved in 120ml DM water) to the filtrate maintaining temperature between 2 to -2°C. The resulting diazotised solution was added to a solution of salicylic acid (63.7g, 0.462mol) in 1280ml DM water containing 30.77g

sodium hydroxide and 81.54g sodium carbonate at 2 to -2°C maintaining pH > 8. After completion of reaction, reaction mass was heated to 60-70°C and pH adjusted to 4.5 using concentrated hydrochloric acid. The reaction mass was maintained at the same temperature for 3 hrs and thereafter it was slowly cooled to 40°C, filtered, washed with water and dried to yield mixture of Balsalazide and its monosodium salt Yield: 121g Chromatographic purity: 99.27% (by HPLC)
EXAMPLE-4
PURIFICATION OF MIXTURE OF 5-[(lE)-[4-[[(2-CARBOXYETHYL)
AMIN01CARB0NYL]-PHENYL]AZ0]-2-HYDR0XYBENZ0IC ACID AND
OF 5-[(lE)-[4-I[(2-CARBOXYETHYL)AMINO]CARBONYL]-
PHENYL]AZO]-2-HYDROXYBENZOIC ACID MONOSODIUM SALT [BALSALAZIDE AND BALSALAZIDE MONOSODIUM SALT MIXTURE] Balsalazide and its monosodium salt mixture (120g) was added to 50%w/v aqueous 1,4-dioxane (360ml) and heated the contents to 90-95°C. After maintaining the mass at 90-95°C for 10 minutes, the suspension was slowly cooled to 60-65°C, filtered, washed with water and dried to yield mixture of Balsalazide and its monosodium salt. Yield: 100g Chromatographic purity: 99.78% (by HPLC)
EXAMPLES
PREPARATION OF S-[(lE)-[4-[t(2-CARBOXYETHYL)AMINO]CARBONYL] -PHENYL] AZO]-2-HYDROXYBENZOIC ACID DISODIUM DIHYDRATE SALT [BALSALAZIDE DISODIUM DIHYDRATE]
A mixture of balsalazide and its mono sodium salt (60g) was added to DM water (180ml) at 25-30°C. Thereafter, the pH of the reaction mass was adjusted to 6.00

using concentrated aqueous sodium carbonate solution, Isopropyl alcohol (300ml)
was added and stirred at the same temperature to obtain a clear solution. The pH of
the reaction mass was adjusted to 6,69 using aqueous sodium carbonate. The clear
solution was decolourised with activated carbon and thereafter, isopropyl alcohol
(1980ml) was added to the filtrate to precipitate the product. The product was filtered,
washed with isopropyl alcohol and dried to yield Balsalazide disodium.
Yield: 68.2g
Chromatographic Purity: 99.86 %
1H NMR (DMS0-d6) δ ppm: 2.16-2.27(q,2H), 3.36(s,2H), 6.73-6,76(d,lH), 7,80-
7.85(m,3H), 7.93-7.96(d,2H), 8.28-8.29(d,2H), 8.95(s,lH), 18.22(s,lH)
EXAMPLE-6
PREPARATION OF 5^[(lE)-[4-[[(2"
CARB0XYETHYL)AMIN01CARB0NYL]-PHENYL]AZ0]-2-HYDROXYBENZOIC ACID DISODIUM DIHYDRATE [BALSALAZIDE DISODIUM DIHYDRATE]
To a suspension of 4-nitrobenzoyl-β-alanine (50g, 0,21mol) in DM water (150ml) sodium hydroxide (8.4g, 0.21mol) was added at 20-25°C and stirred the contents slowly at 20-30°C to obtain a clear solution. Thereafter, the reaction mass was hydrogenated at 20-45°C using Pd/C (l,0g) and at 15-20 Kg/cm2 pressure. After completion of reaction the catalyst was filtered off under nitrogen atmosphere, and diluted with DM water (300ml) thereafter, concentrated hydrochloric acid (65ml 36% w/w, 3.05 meq,) was added to the filtrate at 20-35°C and filter the reaction mass. The filtrate was cooled to 2 to -2°C and added aqueous sodium nitrite solution (15.2g, 0.22 mole in 50ml DM water) maintaining temperature 2 to -2°C. The resulting diazotised solution was added to a solution of salicylic acid (34.72g, 0.252mole in 600ml DM water containing 16,8g sodium hydroxide and 44.52g sodium carbonate) at 2 to -2°C maintaining pH >8. After completion of reaction, reaction mass was

heated to 60-70°C and pH adjusted to 4.2 using concentrated hydrochloric acid. Further, after maintaining temperature at 60-70°C for 3 hours the reaction mass was slowly cooled to 30°C, filtered, washed with water and dried to yield a mixture. Yield: 70g Chromatographic purity: 98.91% (by HPLC)
The above obtained Balsalazide and its monosodium salt mixture (65g) was added to
50%w/v aqueous 1,4-dioxane (195ml) and heated the contents to 90-95°C. After
maintaining temperature 90-95°C for 10 minutes, the suspension was slowly cooled
to 60-65°C, filtered, washed with water and dried to yield mixture of Balsalazide and
its monosodium salt.
Yield: 52g
Chromatographic purity: 99.89% (by HPLC)
A mixture of balsalazide and its mono sodium salt (40g) was added to DM water (120ml) at 25-30°C. Thereafter, the pH of the reaction mass was adjusted to 5.8 using aqueous sodium carbonate solution. Isopropyl alcohol (200ml) was added and stirred the reaction mass at 25-30°C to obtain a clear solution. The pH of the reaction mass was readjusted to 6.8 using aqueous sodium carbonate solution. The reacting, clear solution was decolourised with activated carbon and isopropyl alcohol (1320ml) was added to the filtrate to precipitate the product. The product was filtered, washed with isopropyl alcohol and dried to yield Balsalazide disodium dihydrate. Yield: 45g Chromatographic Purity: 99.96 %

WE CLAIM
1) An improved process for preparing Balsalazide of Formula I,

which comprises,
i) diazotizing 4-aminobenzoyl-β-alanine of Formula IV in DM water, which in situ is reacted with disodiumsalicylate to furnish mixture of Balsalazide of Formula V and its mono sodium salt of Formula VI

with a ratio of 60:40-80:20;
ii) optionally purifying the mixture obtained in step i; and
converting the mixture in to disodium salt to obtain Balsalazide of Formula I.

2) The process according to claim 1, where in 4-aminobenzoyl-β-alanine of
Formula IV is prepared by a process which comprises :
i) halogenating 4-nitrobenzoic acid of Formula II

using halogenating agent in an organic solvent to give 4'nitrobenzoyl chloride, which in situ is reacted with sodium salt of β-alanine in DM water to give 4- nitrobenzoyl-β-alanine of Formula III

ii) isolating and suspending the 4-nitrobenzoyl-^-alanine of Formula III in DM water in the presence of a base and hydrogenating to give 4-aminobenzoyl-β-alanine of Formula IV

iii) optionally isolating the 4-aminobenzoyl-β-alanine of Formula IV.
3) The process according to claim 2, wherein halogenating agent used in step (i)
is selected from thionyl chloride, oxalyl chloride and the organic solvent is
selected from toluene, diisopropyl ether, cyclohexane, methylene dichloride.

4) The process according to claim 1, wherein the organic solvent is selected from toluene, diisopropyl ether, cyclohexane, methylene dichloride.
5) The process according to claim 2, wherein base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide or aqueous ammonia and acid is selected from hydrochloric acid, sulfuric acid, acetic acid.
6) The process according to claim 1, wherein diazotization is carried out using hydrochloric acid and sodium nitrite.
7) The process according to claim 1, wherein the purification is carried using aqueous 1,4-dioxane to yield highly pure Balsalazide acid and its monosodium salt mixture.