Title of Invention

PROCESS FOR THE INDUSTRIAL SYNTHESIS OF BALSALAZIDE DISODIUM DIHYDRATE

Abstract

Abstract: A process for preparation of Balsalazide, particularly Balsalazide disodium dihydrate comprising mixing balsalazide in solvents like water, methanol, or their mixture thereof with aqueous sodium hydroxide to form the disodium salt in a dissolved condition and precipitating disodium salt in its dihydrate solvate form by addition of water miscible anti-solvents selected from polar protic and aprotic solvents is disclosed herein. 21 FEB 2005

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; Rule 13] "Process for preparation of Balsalazide disodium dihydrate" (a) IPCA LABORATORIES LIMITED (b) 48, Kandivli Industrial Estate, Mumbai - 400 067, 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: Technical Field of invention: This invention relates to an improved process for preparation of balsalazide, and more specifically to manufacture of Balsalazide disodium salt, in dihydrate form by a convenient and reproducible process which is economical and plant friendly on an industrial scale. Background of invention: Balsalazide is a colon-specific, non-steroidal, anti-inflammatory aminosalicylate derivative, which is useful in the treatment of gastrointestinal diseases, for example active ulcerative colitis and colon cancer (see WO 95/18622, GB2080796). Balsalazide is basically a prodrug, which upon oral administration, breaks down in the intestinal tract to give its metabolite, aminosalicylic acid, the actual curing agent. Balsalazide is useful for the treatment of ulcerative colitis and has advantage that its breakdown in the intestinal tract doesn't give rise to undesirable metabolic products. The chemical name for balsalazide is 5-(lE) {4-[(2-carboxyethyl) amino] carbonylphenyl] azo}-2-hydroxybenzoic acid. It can be represented by the structure Formula 1(a), Wherein R denotes hydrogen and incase of balsalazide disodium salt, R indicates Sodium. Balsalazide is administered as its disodium dihydrate form in pharmaceutical application. O II C—NH—CH2-CH2—COOR Balsalazide, its preparation, and pharmaceutical use have been disclosed in the patent specification GB2080796 (herein after referred as '796 patent). According to the '796 patent, 4-nitrobenzoyl chloride was reacted with beta-alanine in presence of base like sodium hydroxide, and the resultant nitro compound of Formula II after isolation was reduced by hydrogenation using Palladium catalyst to yield corresponding amino compound (Formula 2 III). The amino compound after diazotization was coupled with salicylic acid to obtain Balsalazide freeacid (Formula 1(a)). This was further converted into disodium salt (Formula 1(b)) in ethanol by reacting with ethanolic sodium hydroxide . Eventhough '796 patent gives a practical route of synthesis of balsalazide, the process suffers from many disadvantages from an industrial scale-up point of view. That is 1. The use of solid 4-nitrobenzoyl chloride as starting material, which is difficult to handle on an industrial scale because of its corrosive and/lachrymator characteristics. Acid chlorides being hygroscopic, irritant and susceptible to hydrolysis make their storage and handling difficult on manufacturing scale and necessitates special provisions. 2. The '796 patent directs the use of costly catalyst like Palladium for carrying out reduction of nitro group, resulting into high cost of production. 3. The main drawback lies in the conversion of balsalazide into balsalazide disodium salt. Balsalazide and its disodium salt are .poorly soluble in most of the organic solvents. The disodium salt formed, according to '796 patent, in ethanol with an ethanolic sodium hydroxide solution resulted into incomplete formation of salt due to heterogeneous state of reactants and product and remain contaminated with some unreacted free balsalazide in the balsalazide disodium salt. The incomplete salt formation also gets reflected in variation of its physical characteristic such as color. 4. Balsalazide is administered as its disodium dihydrate salt form in pharmaceutical application. And there is no prior art available to give a reliable method for the production of balsalazide disodium salt in its dihydrate form to get consistent results. A subsequent disclosure in a journal, Zhongguo Yaown Huaxue Zhazhi 2001, 11(2), pp.110-111 (Ch), for which no details could be available^ talks about an improvement in the process for balsalazide. Objectives of the invention: It is therefore an objective of the present invention to provide an improved process for the manufacture of balsalazide and its disodium salt from starting materials that are readily available commercially, relatively inexpensive, and relatively safe to use. Another major objective is to find a process for the specific and complete formation, and isolation of disodium salt of balsalazide in dihydrate form in a convenient and reproducible manner. Yet another objective is to reduce the cost of manufacture by developing a reducing method for the reduction of nitro intermediate by using cheaper catalyst like Raney Ni. 3 Summary of the invention: The present invention features an improved process for preparing balsalazide and its disodium salt by reagents safer to handle on an industrial scale. Balsalazide disodium salt is prepared by forming the disodium salt in solvent like water, methanol or their mixture thereof by mixing balsalazide in solvent with aqueous sodium hydroxide to ensure the complete salt generation in a dissolved condition and then precipitating disodium salt in its dihydrate solvate form by addition of water miscible anti-solvents selected form polar solvents. In another aspect, the invention provides a process where 4-nitrobenzoyl chloride is generated in situ and reacted with beta-alanine starting from 4-nitrobenzoic acid to give the compound of Formula II. In one of the embodiments, the present invention provides a cost effective alternative to palladium catalyst by hydrogenating a compound of Formula II using Raney Nickel as hydrogenarion_catelysJjn,alcoh©>Kc solvents to give the compound of Formula III In another preferred embodiment balsalazide free acid of Formula I (a) is isolated, after diazotization and coupling with salicylic acid, at a pH of 3.5 to 4.5 to get higher purity. In yet another preferred embodiment, the balsalazide disodium salt is prepared and isolated in its pure dihydrate form at a pH of 9.4- 9.9 by titrating balsalazide freeacid with aqueous sodium hydroxide to a homogeneous solution and precipitating it using an anti-solvent. This process gives consistent quality with respect to colour as well as purity. Other features or advantages of the present invention will be apparent from the following detailed description of the invention, and also from the appending claims. Detailed description of the invention. The present invention provides an improved process for the manufacture of balsalazide and its disodium salt in dihydrate form. 4 In the process, according to the present invention, 4-nitrobenzoic acid is converted to its acid chloride by reacting with chlorinating agents like thionyl chloride in solvents such as hydrocarbon solvent like toluene, or chlorinated solvents like ethylene chloride under reflux or heating at a temperature of 40°-100° C. The mostpreferred solvent is toluene. After completion of the reaction excess thionyl chloride and parts of the solvent are removed by distillation. The 4-nitrobenzoyl chloride solution so obtained in toluene is reacted in situ with beta-alanine in presence of aqueous base such as alkali metal hydroxides or carbonates or organic bases like triethyl amine. Alkali metal hydroxides referred above are independently O NH-CH2CH2COOH N02 Formula II sodium hydroxide, potassium hydroxide and carbonates are independently sodium carbonate or bicarbonate and potassium carbonate or bicarbonate. The preferred base used is sodium hydroxide asjm aqueous solution. The compound of Formula II obtained after normal work¬up is purified in alcoholic solvents like isopropyl alcohol. In the process of the present invention, the compound of Formula II thus obtained is dissolved in solvents like Q-C3 alcohols and hydrogenated using Raney Nickel as the catalyst under conditions effective to yield compound of Formula III. O NH-CH2CH2COOH Formula III The hydrogenation temperature employed in the present invention is maintained in the range of 30° - 60° C and a hydrogenation pressure of 8 -12 Kg/cm2 is required to effect the transformation. The most preferred hydrogenation pressure is 10 Kg/cm2. The C1-C3 5 alcoholic solvents are selected from methanol, ethanol, isopropyl alcohol etc., but preferably the solvent is methanol, although not critical, but for better solubility. On completion of hydrogenation, the compound of Formula III is isolated by normal work-up from the reaction mixture, i.e. filtration of catalyst, and removal of solvent. The compound of Formula III is then diazotized by conventional method ('796 patent) using cone. Hydrochloric acid and Sodium nitrite in aqueous conditions and the diazonium salt formed is coupled with salicylic acid under basic conditions. On completion of reaction the reaction mass is adjusted to acidic pH for isolation of balsalazide free acid. It is observed that the direct isolation of balsalazide free acid from the reaction mixture at varying pH resulted in lower purity, which is essential in the final conversion to disodium salt for consistent color and purity. So in accordance with the invention, after completion of the reaction the pH of the solution is adjusted in the range of 2.5 to 5, preferably in the range of 3.5 to 4.5 using dil. Hydrochloric acid. This adjustment of pH is necessary to get higher purity of balsalazide in satisfactory yields. After filtration of free acid, it is leached using aqueous ethanol and the product after drying is used in the subsequent step. After extensive research the present inventors found that the salt formation stage is equally important to get a pure material in the final stage. It is also found that the isolation of balsalazide at a specific pH, and titration and isolation of balsalazide with alkali in a specific pH range operating condition in homogeneous solution can solve the problems in the prior art. Due to the poor solubility of balsalazide (free acid of Formula I (a)) and its disodium salt in most of the organic solvents, the disodium salt formation and precipitation requires precise conditions to get the disodium salt exclusively and that necessitates solubilizing agents or a solvent, where disodium salt is completely soluble. But then the crystallization of disodium salt in dihydrate form from these solvents resulted in yield losses. In this aspect, the present invention provides a process by reacting the balsalazide free acid with the required quantities of aqueous sodium hydroxide in solvents like water, methanol or their mixture thereof. The disodium salt of balsalazide is highly soluble in water and this is advantageously used in the present invention for the salt formation. The salt formation is 6 effected at a temperature of 25° - 50° C and completed when the pH is in the range of 9.4 to 9.9. The most preferable pH for the isolation of disodium salt is 9.6 to 9.8. The most preferred solvent for the salt formation is water, which is a non-noxious solvent. After complete formation of balsalazide disodium salt, the dihydrate form of balsalazide disodium salt is precipitated by addition of a water miscible anti-solvent. The anti-solvents used for the precipitation in the present inventions are selected from polar protic and aprotic solvents. Polar protic solvents are selected from C2-C4 alcohols in all its isomeric forms and polar aprotic solvents selected from acetonitrile, ketonic solvents like acetone, ether solvents like tetrahydrofuran and 1,4-dioxane. The C2-C4 includes ethanol, 1-propanol, n-butanol, isopropylalcohol, tertiary butylalcohol, isobutylalcohol. The anti-solvents advantageously used in the present invention are ethanol or isopropyl alcohol. In an alternative variant of the present invention the balsalazide salt solution is added into the anti-solvent to precipitate the disodium dihydrate of balsalazide. In the process, the precipitation by anti-solvent is preferably carried out at ambient temperature. The volume of water used in the salt formation is preferably in the range of 1.25 to 2.0 volumes with respect to the balsalazide free acid used. The volume of anti solvent used in the precipitation of balsalazide is preferably in the range of 15 to 20 volumes. Since the final API is in dihydrate form, by following the present invention the dihydrate form of balsalazide disodium salt can be produced reproducibly on large scale in higher purity, with consistent physical characteristic like color. The following actual example further illustrates the present invention without limiting its scope. Any modification and substitution easily recognized by persons skilled in the art are within the scope and the spirit of the present invention. EXAMPLES: Example - 1 : (4-nitrobenzoyl-beta-alanine - Formula II) In a reaction vessel, 400 gm. (2.39 moles) of 4-nitrobenzoic acid and 1.0 litre toluene were taken. To this 16 ml. of N, N-Dimethylformamide were added and the mixture heated to 60- 65°C and 521.6 gm. (4.38 moles) of thionyl chloride were added at 60-65°C. The reaction 7 mass was refluxed for about 6 hours. About 70% of toluene was distilled to remove excess thionyl chloride. This was added to a solution of beto-alanine 266.64 gm. (2.99 moles) in aqueous sodium hydroxide solution (282.4 gm., 7.06 moles; water 1.8 litre) while maintaining the temperature at 0 to - 5°C. After addition the temperature was raised to about 25°C and maintained for about 2.0 hours. The reaction mass was quenched in ice containing concentrated hydrochloric acid. The precipitated product was filtered off and washed with water, suck dried. Weight of dry crude product was 540 gm. The crude product was purified using isopropyl alcohol to give 467 gm. (yield - 82%) of compound of Formula II. Example - 2 (4-aminobenzoyl-beta-alanine - Formula HI) 200 gm. (0.84 moles) of compound of Formula II obtained as per the Example -1, and methanol (2.80 litre) were taken in autoclave. 13.2 gm of Raney-Ni were added to it. Hydrogen gas (about 10 kg. /cm2 pressure) was taken at about 30°C. The temperature was increased to about 45°C. After completion of reaction, the catalyst was filtered off; solvent was removed under vacuum to get 168 gm (yield - 96%) of compound of Formula III Example - 3 (Balsalazide free acid - Formula 1(a)) In a reaction vessel, compound of Formula III (100 gm, 0.48 moles), were taken in 136 ml. of concentrated hydrochloric acid. 900 ml. water were added to it under stirring and the solution was cooled to -5°C. A solution of 137 gm. sodium nitrite in 250 ml. water was added dropwise at 0 to -5°C. The diazotised mass was left for about 1.5 hours at 0 to -5°C. The excess sodium nitrite was decomposed by adding aqueous solution of urea. The diazotized solution was added to a solution of salicylic acid (69.5 gm, 0.50 moles), 136 gm. of sodium carbonate, 40 gm. sodium hydroxide in about 1.5 litre water at 0 to -5°C. The reaction mass was maintained at 0 to -5°C for about 3 hours and then warmed to around 40°C. Concentrated hydrochloric acid was added to get a pH of 4.5. The precipitated product was filtered off, washed with water followed by slurry wash using aqueous ethanol to get 130 gm. (yield - 75%) of balsalazide free acid. Example - 4 (Balsalazide disodium dihvdrate) In a reaction vessel, 75 gm. (0.21 mole) of Balsalazide free acid obtained as above, was mixed with a solution of sodium hydroxide (prepared by mixing 16.65gm. sodium hydroxide & 112.5 ml. water) was added slowly. The pH adjusted to 9.6 - 9.8. The salt solution formed was filtered. To the filtrate, about 1.36 litre of isopropyl alcohol was added. The precipitated 8 product was filtered off, suck dried & dried to get 88 gm. (yield - 95%) of balsalazide disodium dihydrate. Example - 5 (Balsalazide disodium dihydrate^) In a reaction vessel, 75 gm. (0.21 mole) of Balsalazide free acid obtained as above, was mixed with a solution of sodium hydroxide (prepared by mixing 16.65gm. sodium hydroxide & 112.5 ml. water) was added slowly. The pH adjusted to 9.6 - 9.8. The salt solution formed was filtered. To the filtrate, about 1.36 litre of acetone was added. The precipitated product was filtered off, suck dried & dried to get 88 gm. (yield - 95%) of balsalazide disodium dihydrate. Example - 6 (Balsalazide disodium dihydrate) In a reaction vessel, 75 gm. (0.21 mole) of Balsalazide free acid obtained as above, was mixed with a solution of sodium hydroxide (prepared by mixing 16.65gm. sodium hydroxide & 112.5 ml. water) was added slowly. The pH adjusted to 9.6 - 9.8. The salt solution formed was filtered. To the filtrate, about 1.80 litre of acetonitrile was added. The precipitated product was filtered off, suck dried & dried to get 78 gm. (yield - 85%) of balsalazide disodium dihydrate. We claim, 1. A process for the preparation of balsalazide disodium dihydrate of the Formula 1C comprising steps of; i) generation of 4- nitrobenzoyl chloride from 4-nitrobenzoic acid using a chlorinating agent and in situ reaction with beta-alanine in presence of an organic or inorganic base and isolating a compound of Formula II, ii) hydrogenation of the compound of Formula II to form a compound of Formula III in presence of Raney Ni catalyst in solvents selected form C1-C3 alcohols, iii) diazotization of compound of Formula III using hydrochloric acid-sodium nitrite and coupling of the resulting diazonium chloride intermediate with salicylic acid characterized in that the isolation of pure balsalazide of Formula I (a) from the reaction mixture is carried out at a pH of 2.5 to 5.0, and iv) reaction of balsalazide free acid of Formula 1(a) in water with aqueous sodium hydroxide sufficient to effect balsalazide disodium salt in solution and isolating compound of Formula 1C in dihydrate form by addition of anti-solvent. 2. The process as claimed in claim 1, wherein the anti-solvents used in the precipitation of balsalazide disodium dihydrate are water miscible polar protic and aprotic solvents. 3. The process as claimed in claim 1 or 2, wherein the polar protic solvents are C2-C4 straight chain or branched chain alcohols, and polar aprotic solvents are acetonitrile, ketonic solvents like acetone, and ether solvents like tetrahydrofuran and 1,4-dioxane. 4. The process as claimed in claim 3, wherein the anti-solvent is isopropyl alcohol. 5. The process as claimed in claim l(i) wherein 4-nitrobenzoyl chloride is generated by reaction of 4-nitrobenzoic acid with a chlorinating agent. 6. The process as claimed in claim 5, wherein said chlorinating agent is thionylchloride. 7. The process as claimed in claim 1 (i), 5 and 6 wherein the chlorination is carried out in hydrocarbon solvent or chlorinated hydrocarbon solvents. 8. The process as claimed in claim 7, wherein the solvent used in the acid chloride formation is toluene. 9. The process as claimed in claim l(i), wherein the organic base is triethyl amine, and the inorganic base is selected from alkali metal hydroxides and alkali metal carbonates. 10. The process as claimed in claim l(ii) wherein, the 4-nitrobenzoyl beta-alanine of Formula II is purified using isopropyl alcohol. 11. The process as claimed in claim l(ii) wherein, the C1-C3 alcohols are methanol, ethanol, and isopropyl alcohol. 12. The process as claimed in claim 11 wherein, the hydrogenation is carried out at a temperature of 30° to 60° C and a hydrogenation pressure of 10 to 12 kg/cm2 13. The process as claimed in claim l(iv), wherein the disodium salt formation is effected at a temperature of 25° to 50 °C. 14. The process as claimed in claim 13 or l(iv), wherein the isolation of balsalazide disodium dihydrate is carried out at pH of 9.4 to 9.9. 15. The process as claimed in claim l(iii), wherein the balsalazide diacid of Formula I (a) is isolated at pH of 3.5 to 4.5. 16. A process for preparation of balsalazide disodium dihydrate salt of Formula 1C comprising reacting balsalazide of Formula 1(a) in water with aqueous sodium hydroxide solution till a pH of 9.4 to 9.9 and isolating the said salt from the water solution by precipitation using a water miscible anti-solvent. II 17. A process for preparation of Balsalazide disodium dihydrate salt and its intermediates as substantially described herein with reference to the foregoing examples 1 to 6. Dated this the 5th day of July 2004

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713-mum-2004-abstract(21-2-2005).doc

713-mum-2004-abstract(21-2-2005).pdf

713-mum-2004-cancelled pages(21-2-2005).pdf

713-mum-2004-claims(granted)-(21-2-2005).doc

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713-mum-2004-correspondence(21-2-2005).pdf

713-mum-2004-correspondence(ipo)-(29-11-2004).pdf

713-mum-2004-form 1(14-7-2004).pdf

713-mum-2004-form 1(21-2-2005).pdf

713-mum-2004-form 1(5-7-2004).pdf

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713-mum-2004-form 2(granted)-(21-2-2005).doc

713-mum-2004-form 2(granted)-(21-2-2005).pdf

713-mum-2004-form 26(9-4-2003).pdf

713-mum-2004-form 3(5-7-2004).pdf